Schisis

Initiatief: NVPC Aantal modules: 51

Genetische diagnostiek bij schisis

Uitgangsvraag

Wat is de opbrengst van verschillende genetische testen bij patiënten met geïsoleerde lip-, kaak en/of palatumschisis?

Aanbeveling

Aanbeveling voor de arts/professional die schisis vaststelt

Bespreek met iedere schisispatiënt en/of ouders van iedere schisispatiënt (geboren/ongeboren):

  • dat bij schisis genetische factoren een rol kunnen spelen
  • de mogelijkheid van een verwijzing naar een klinisch geneticus (bij voorkeur verbonden aan een schisisteam) om de mogelijkheden te bespreken van:
    1. genetische diagnostiek
    2. herhalingskans
    3. prenatale diagnostiek

 

Bespoedig de verwijzing bij een postnataal vastgestelde schisis naar een klinisch geneticus indien sprake is van bijkomende problemen zoals groei- en voedingsproblemen, geassocieerde afwijkingen, ontwikkelingsachterstand, specifieke verdenking op een syndroomdiagnose en/of chromosoomafwijking.

 

Aanbeveling voor de klinisch geneticus/medisch specialist

Laat bij genetische counseling met de patiënt/ouders de volgende onderwerpen aan bod komen:

  • Anamnese en familieanamnese gericht op schisis
  • Voer bij een vastgestelde schisis een lichamelijk en dysmorfologische onderzoek uit en maak klinische foto’s
  • Bespreek de optie van genetische diagnostiek
  • Bespreek dat de opbrengst van genetische diagnostiek kan afhangen van type schisis en andere bijkomende aangeboren afwijkingen en belaste familieanamnese
  • Bespreek de mogelijkheden van eventueel onduidelijke uitslagen of nevenbevindingen.
  • Bespreek de mogelijkheid van opslag DNA uit navelstrengbloed of bloedafname bij operatie dat gebruikt kan worden voor toekomstig DNA onderzoek.

 

Streef naar gepersonaliseerde genetische diagnostiek en neem bij de keuze tot een bepaalde genetische test in overweging:

  • type schisis
  • aanwezigheid van bijkomende verschijnselen
  • familieanamnese.

 

Zie voor een handvat in keuze genetische test “Aanbeveling voor optimale strategie voor genetische diagnostiek bij schisis en organisatie van genetische diagnostiek”.

 

Verwijs patiënten en/of ouders naar websites/andere informatiebronnen over genetische diagnostiek/onduidelijke en nevenbevindingen.

 

Verwijs patiënten en/of ouders naar zorgprofessionals of Schisis Nederland voor informatievoorziening betreffende diagnostiek, psychosociale begeleiding en lotgenotencontact.

 

Aanbeveling voor optimale strategie voor genetische diagnostiek bij schisis en organisatie van genetische diagnostiek

Neem bij de keuze tot een bepaalde genetische test het type schisis, de aanwezigheid van bijkomende verschijnselen en familieanamnese mee in de overweging.

Neem als handvat onderstaande strategie mee in de keuze tot de genetisch test.

 

Geïsoloeerde CLA:

  1.  overweeg schisisgenpanel analyse in trio (incl. CVN analyse)

 

Geïsoleerde CLA/P en CP:

  1.  schisisgenpanel analyse (incl. CNV analyse) in trio
  2.  overwegen aanvulling met SNP array en/of andere genpanels

 

Geïsoleerde CLA/PS met belaste familieanamnese

  1. schisisgenpanel analyse (incl. CNV analyse)
  2. overweeg uitbreiding met SNP array en/of andere genpanels – evt. aansluitend met open exoom analyse.

 

CL, CL/P of CLA/PS met geassocieerde afwijkingen en/of verdenking chromosomale afwijking

  1. SNP array
  2. Schisis genpanel analyse in trio, zo nodig in aanvulling met andere genpanels, met aansluitend open exoom analyse, indien sterke verdenking/VUSsen aangevuld met RNA-analyse/ whole genome sequencing/testen ander weefsel etc.

 

Organisatie van genetische diagnostiek

Voer met betrokken klinisch geneticus en laboratoriumspecialist overleg over (her)classificatie van gevonden genetische varianten waarvan klinische betekenis onduidelijk is (in multidisciplinair verband).

 

Informeer de laboratoriumspecialist over:

  • de conclusie ten aanzien van de (syndroom)diagnostiek
  • aanpassing van de classificatie van de VUS op basis van kliniek of verricht segregatieonderzoek binnen de familie.

 

Overweeg binnen het laboratorium een jaarlijkse evaluatie uit van de resultaten van de uitgevoerde genetische onderzoeken, zodat inzicht wordt verkregen in de opbrengsten van de verrichte diagnostiek.

 

Vorm een landelijke multidisciplinaire schisiswerkgroep (vanuit VKGN, VKGL, NVSCA) en organiseer een overleg tussen de verschillende expertisecentra zodat complexe genetische uitslagen kunnen worden besproken.

 

Overweeg een landelijke database op te richten, op grond waarvan een genotype fenotype correlaties kunnen worden vastgesteld en die zal bijdragen aan de interpretatie van VUS-en.

Overwegingen

Advantages and disadvantages of diagnostic tests

Despite no studies were found in which the yield of different diagnostic tests in isolated clefts of the lip and/or palate has been compared, studies do provide information about the different diagnostic genetic tests.

 

In general, the diagnostic tests could be divided into two types; array-based methods (identifying minor chromosomal anomalies; microdeletions and microduplications) and sequencing methods (identifying gene variants).

 

Copy number variant analyses (invasive genetic testing)

Large structural alterations of the genome and deletions and duplications of genomic regions termed copy number variations (CNVs), have been studied in CLA/P patients using classical genetic analyses such as FISH, array CGH or, more recently, SNP arrays (Conte, 2016). Also, some studies mention karyotyping; identifying numerical and large chromosomal anomalies. However, small microdeletions and - duplications will be missed by conventional karyotyping.

 

Maarse (2012) conducted a systematic review to provide a basis for prenatal invasive diagnostics by investigating the prenatal and postnatal prevalence of associated anomalies and chromosomal defects related to CLA/P. They provided a systematic search and used data from the Dutch Oral Cleft Registry to investigate the prevalence of associated anomalies and chromosomal defects both prenatal and postnatal. This review also provided recommendations for diagnostic genetic testing for different types of CLA/P. This review included 20 studies: 3 prenatal, 13 postnatal and 4 combined. This review concluded that array CGH should be considered in case of isolated oral cleft lip on prenatal ultrasound, because the absence of associated anomalies does not exclude the possibility of the presence of an underlying chromosomal defect. The chance of finding chromosomal deficits seems to depend on the type of CLA/P. For example, in presumed isolated CLAP or CP array-based methods are recommended. However, it should be considered that genetic techniques included in the review of Maarse (2012) are nowadays at least (partially) replaced by newer diagnostic genetics tests.

 

The study of Szczaluba (2015) assessed the utility of array comparative genomic hybridization in 53 Polish newborns with presumed isolated CLA/P. Szczaluba identified 8 unique CNVs in a total of 8/52 patients (15%) using array CGH, including 3 deletions and 5 duplications. The largest rearrangement could be confirmed by karyotyping.

 

The study of Cao (2016) highly recommends chromosomal microarray analysis (CMA) in prenatal invasive genetic testing, not only for syndromic oral cleft cases but also for non-syndromic cases with soft markers in ultrasound (such as a single umbilical artery). CMA is a variant of array CGH/ SNP array method. The CMA analysis showed an improved detection rate of 15.3% for pathogenic copy-number variants compared with 10.5% for conventional chromosome analysis. Candidate genes including CRKL, AKAP8, SYDE1, BRD4 are worthy of further investigation regarding their role in human palatogenesis.

 

In the study of Conte (2016) 45 potential candidate genes for deletions and 27 for duplications were found, including several known causative genes for CLA/P, such as SATB2 and MEIS2, and genes that are associated with CLA/P or development of CLA/P. This study found 34 deletions and 24 duplications in genes that have not previously been associated with CLA/P.

 

In conclusion, the above discussed studies demonstrate genetic testing (incuding karyotyping, FISH, array CGH, and SNP array) can reveal structural and numerical chromosomal anomalies and CNV’s in CLA/P cases. However, the studied population and the genetic techniques differed between the different studies. Even, the resolution of the SNP array analyses can differ between laboratories. Therefore, the outcome of these studies can not be compared.

 

Next-generation sequencing methods

Next-generation sequencing methods like whole exome sequencing (WES) in family-based designs offer important advantages for identifying gene variants causing complex and heterogeneous disorders like CLA/P (Bureau, 2014, Basha, 2018).

 

Bureau (2014) conducted a study with WES to search for variants causing CLA/P using affected relatives from 55 multiplex families. Rare single nucleotide variants (SNVs), detected with WES, shared by affected relatives in 348 recognized candidate genes were examined. These 348 candidate genes consisted of 334 autosomal candidate genes for oral clefts (Jugessur, 2009) plus 14 recently confirmed genes and regions yielding genome-wide significance in a meta-analysis (Ludwig, 2012) and a replication study (Beaty, 2013). Bureau (2014) found five novel and potentially damaging SNVs shared by affected distant relatives (CDH1, FGF8, FGFR4, TRPS1, FTCD). One damaging SNV in CDH1 was shared by three affected second cousins from a single family, indicating that this SNV is very unlikely to occur by chance alone.

 

The study of Basha (2018) also reports on gene variants causing syndromic CL/P using WES. They tested a cohort of 84 individuals diagnosed with non-syndromic CL/P from multiplex families (n=46) to find rare variants in genes causing syndromic CL/P. Patients included in this study had a normal karyotype, the majority had been tested for a 22q11.2 deletion and anIRF6 mutation (Van der Woude syndrome). Patients were diagnosed with bilateral CL/P (n=7), unilateral CL/P (n=16), unilateral cleft lip (CL)(n=8), cleft palate (CP)(n=33), CP-posterior (n=7), submucous cleft palate (SMCP)(n=2), SMCP with bifid uvula (n=2) and velopharyngeal insufficiency (n=9). Genetic variants were analyzed independently in each family and each subject. The following four mutations were found in four different genes in five patients: TP63 (1 family), TXC1 (one family), LRP6 (one family) and GRHL3 (two families). The four mutations co-segregated with the oral cleft in an autosomal dominant manner in all families. This study shows that patients diagnosed with isolated CL/P still can carry a mutated gene causing the CL/P, whole-exome sequencing (WES) / next generation sequencing is therefore recommended when there is a family history with CL/P (Basha, 2018). In 10% of the patients with non-syndromic CL/P with a positive family history a causative Mendelian mutation could be identified. It could be that in an important percentage of the remaining cases, the same genes are involved due to an indel or copy number alteration (CNVs) not easily detectable by WES. Whole genome sequencing will therefore likely be the best choice for diagnostic screens of families with a history of non-syndromic CL/P (Basha, 2018).

 

WES is increasingly used in the Netherlands in both isolated as syndromic CLA/P. In the Netherlands, however different strategies are used in the cleft centers arout the country. At first, a cleft gene panel analysis can be done. When multiple congenital anomalies are present, analyses of all OMIM morbid genes (based on WES) or a complete trio WES with analyses of the total exome (open exome) can be performed. In trio WES analyses DNA of the parents is included. These tests are offered in a postnatal, but also in a prenatal setting. Gene panels do have differences regarding content, filtering (single versus trio analysis) and classification of variants can differ among centers.

 

Recently, a retrospective study was performed to obtain insight in the diagnostic yield of cleft gene panel analyses in UMCU (unpublished data). The yield of the gene panel analysis was evaluated from 2015-2020. In this period the gene panel was updated, and the number of genes included in the gene panel is expanded (156 to 195 cleft related genes) (https://www.umcutrecht.nl/nl/next-generation-sequencing-ngs).

 

In this study 212 CLA/P patients were included. Most genetic tests were done for CP (103, 48.6%), followed by CLA/P (77, 36,3%) and CL (25, 11,8%). In 7 cases (3.3%) cleft type was not defined. All cases underwent cleft gene panel analyses and, in some cases, additional genetic testing (for example ID gene panel, mendeliome or trio WES) was performed.

 

Cleft gene panel analyses revealed a genetic (syndromic) diagnose, by identification of a pathogenic variant (P) and clinical confirmation of the diagnosis in 11.3 % (24/212) of the cases. Classification of a gene variant of unkown significance (VUS) often required integrated analyses of genetic and clinical data (including pedigree) and regularly subsequent segregation analyses in the family had to be performed.

In (3.8 % (8/212) a causative genetic diagnosis was confirmed by additional genetic testing. Most genetic diagnoses could be confirmed in CP cases (50 %, n=16); versus CL(A)+P) (40.6 %, n=11) and CL (9.4 %, n=3). In one case the cleft type was not defined.

 

We realize this retrospective inventory probably reflects the outcome of a biased population, because in general practice genetic testing is probably more often performed in children with additional minor or major anomalies or congenital abnormalities and in cases with a positive family history for clefting.

 

In addition to genepanel analyses and WES, genome wide methylation tests (Episign ©) can be offered to confirm a suspected diagnosis, associated with a specific methylation profile (Aref-Eshghi, 2019; 2020).

 

Summary

In conclusion, previous studies and the inventory of a Dutch cleft population (n=212) demonstrated broad genetic testing can reveal underlying genetic diagnosis in syndromic clefting but also in cases with (apparent) nonsyndromic isolated clefting. Additional anomalies and family history of clefting might indicate an underlying genetic cause of the cleft. The genetic diagnoses are most frequently identified in cases with CP and CLA/P.

 

Unfortunately, the current literature does not provide information about the exact yield of different diagnostic genetic tests in an unbiased well subphenotyped cleft population. More specific, the type of clefting in these studies are not uniformly subclassified according the subclassification proposed by Dixon (2011), Mc Bride (2016), Pool (2021) and Vermeij-Keers (2018). Furthermore, the genetic techniques differed between the various available studies.

 

Further studies, including broad genotype-phenotype evaluation in well subphenotyped population and treatment outcome studies, are necessary to define those children in which genetic testing will have most benefit and determine the optimal strategy of genetic testing in cleft cases.

On the other hand, literature and the retrospective study conducted by UMCU showed that (complex) genetic testing can prevent a long Diagnostic Odyssey. Furthermore, identification of genetic anomalies will allow tailored medical care.

 

Values and preferences of patients and their parents or guardians

While genetic testing can reveal a genetic cause of CLA/P requiring specific medical care, the advice is to refer all patients with CLA/P (pre- and postnatally), with consent of patient and/or parents, to a department of genetics for genetic counseling. So, they can be informed about the genetic aspects of CLA/P, genetic testing, their recurrence risk, and prenatal diagnostics.

 

It is of great importance that genetic testing is based on shared decision making and personalized medicine, where clinicians (clinical geneticist, gynaecologist, and/or plastic surgeon) and patients work together to make individual decisions about invasive prenatal diagnostics and the choice of the genetic test. In this process the outcome is based on clinical evidence and expected outcomes with inclusion of patients and/or parents’ preferences and values.

 

Parents of children with CLA/P and patients with CLA/P should be informed about all options of genetic testing with the pro and cons, including information on incidental findings, and the possibilities of advanced ultrasound research. After consultation it remains to the parents to decide about (further) diagnostic testing.

 

Professionals should realize that some parents and/or patients do not prefer invasive prenatal testing when a CLA/P is observed in an unborn child and individual considerations of pregnant couples can differ enormously. Also, religion can play a significant role in the decision-making process. However, referral of parents with a fetus with CLA/P to a clinical geneticist is important to discuss the options for further clinical genetic testing and outcomes of these tests.

 

Guidance of parents in this process is of great importance. Moreover, some parents might be confronted with a severe (lethal) disorder in their child and must decide on continuation or termination of pregnancy (TOP). However, it is also possible that a clinical genetic diagnosis helps in deciding for optimal peri- and postnatal care.

 

Parents of a child with CLA/P and patients with CLA/P, should also be informed about their recurrence risk and options for future pregnancies, e.g. preimplantation genetic testing (PGD). Furthermore, it is important that parents and future parents are aware of their right to get a second opinion and they can contact patients organizations for more information and empowerment, for example in the Netherlands: www.schisisnederland.nl, http://www.erfelijkheid.nl/(date: May 2021).

 

Costs/Finances

With clinical application of whole-exome and whole-genome sequencing in CLA/P cases a diagnosis can be made in an early stage, preventing a Diagnostic Odyssey. Also initially in presumed isolated clefts.

 

The Dutch Health Council indicates that early diagnosis is extremely important. Knowing the genetic origin will lead to better treatment and timely interference for possible future symptoms related to their genetic disorder. Moreover, early diagnosis prevents unnecessary second opinions and additional diagnostic tests and can thus limit the negative consequences for the well-being of the child and the parents. Futher, parents can be informed about risks of recurrence.

 

The Dutch Health Council states that early genetic testing should be used instead of introducing heel prick screening for untreatable conditions.

 

On the other hand, an early diagnosis can also be stressful for the parents, while it may take a long time for symptoms to arise. Also, the clinical spectrum of certain diagnoses can be broad, which can create uncertainty.

 

DNA testing in the Netherlands is totally reimbursed by the basic insurance, however, the mandatory excess will be paid first. It is important that patients are informed about reimbursement rules.

 

The actual cost-effectiveness of genetic testing cannot be determined until the yield of genetic testing has been determined in an unbiased population, and follow-up studies have been performed to analyse the effect of a specific diagnosis, considering the quality of life of people with CLA/P and their parents.

 

Acceptance, feasibility and implementation

Nowadays, genetic counselling and testing is increasingly offered to (future) parents of a child with CLA/P in both prenatal and postnatal settings. We have inquired at our eight genetic centres which policy they currently used. The outcome demonstrated all centres, despite variations variations in genetic strategy, discussed and offered genetic testing.

The clinical geneticist is not always present during consultation at the prenatal or postnatal cleft team. When (future) parents opt for genetic testing, they are referred to the genetics department and receive an invitation for a separate consultation. Depending on personal, cultural, and familial considerations and possible consequences, parents can decide which genetic testing will be performed. This decision should be made on accurate information, therefore shared decision making, and counselling is essential, and even more important than diagnostic outcome.

 

Rationale

1. Aanbeveling voor de arts/professional die schisis vaststelt

The review of Maarse (2012) and the inventory of the outcome of genetic analyses in a Dutch cleft population (unpublished data) demonstrates genetic testing can identify (extreme) rare genetic disorders. Confirmation of a genetic diagnosis can optimize personalized, timely car and improve medical and genetic counselling.

 

In prenatlly detected CLA/P, advanced ultrasound (GUO) and genetic testing can lead to an underlying diagnosis.

To inform parents of a child with CLA/P or patients with CLA/P about the pros and cons of genetic testing and to promote personalized genetic testing, they should be offered rererral to a genetic department.

 

2. Aanbeveling voor de klinisch geneticus/medisch specialist

Most studies showed that CLA/P and CP are more often associated with an underlying genetic diagnosis. The presence of additional anomalies and/or a positive family history for orofacial clefting can indicate an underlying genetic cause Certain diagnoses (e.g.CDH1, IRF6, SIX3) are associated with variable expression and reduced penetrance.

 

Therefore, genetic counseling should entail an extensive medical and family history, specific physical examination and dysmorphological evaluation of index and their parents (see attachment “intakeformulier”, in Dutch).

 

The strategy of genetic testing in CLA/P should be personalized. The type of cleft, the presence of possible additional minor and major anomalies or abnormalities and the family history must be considered in selecting the best fitting genetic test(s). Moreover, genetic testing can be different in prenatal or postnatal setting. When a cleft is detected prenatally, DNA can be stored from umbilical cord blood for future genetic testing. After birth, blood samples can be taken during surgery. This prevents invasive bloodsampling in the child after birth.

 

A suggested strategy for the genetic diagnostics is discussed in “Aanbeveling voor optimale strategie voor genetische diagnostiek bij schisis en organisatie van genetische diagnostiek” in this module.

 

One should realize sequential DNA testing can be associated with increased costs and extensive DNA testing might increase the chance detecting variants of uncertain (or unknown) significance or unsolicited findings. In addition, an important aspect to keep in mind using next-generation sequencing technologies such as WES trio analysis, is that autosomal dominant gene variants with a reduced penetrance (e.g.CDH1, IRF6, SIX3) segregating in a family, might be filtered out in the data analyses.

 

It is important that parents of a child with CL(A)/P and patients with CL(A)/P are informed about the different aspects of DNA testing, including yield for different cleft type, broad spectrum of cleft syndromes that might be identified, variablility in severity of those syndromes even within families that and the possible identification of variants of uncertain (or unknown) significance. Parents can be referred to informative websites for more information (e.g. Schisis Nederland and Erfocentrum). Parents of a child with CL(A)/P and patients with CL(A)/P should be informed about their recurrence risk and possible choices concerning future pregnancies.

 

3. Aanbeveling voor optimale strategie voor genetische diagnostiek bij schisis en organisatie van genetische diagnostiek

Genetic testing should be personalized and the type of clefting, additional anamolies and family history should be considered. The strategy, described below, should be considered.

 

In CLA/P cases, suspected of an underlying chromosomal abnormality, SNP array is the first choice of testing.

In CLA/P cases, without a suspected syndrome diagnosis or chromosomal abnormality, cleft gene panel analyses, including CNV analyses, (WES targeting cleft related genes) should be considered as the first choice of genetic testing. By performing a trio WES, inherited variants with reduced penetrance and/or variable expression segregating in a family might be filtered out and can be missed.

In CLA/P cases with associated anomalies combined SNP array and WES based cleft gene panel analyses (including CNV analyses) should be considered.

In cases with specific dysmorphic features and/or associated congenital anomalies and/or intellectual disability broader genetic testing (for example for ID and/ or congenital anomalies, mendeliome), specific single gene sequencing and additional trio WES) should be considered.

In case of a prenatally diagnosed CLA/P, prenatal invasive diagnostics is offered (chorionic villus test / amniocentesis). Based on the presence of additional ultrasound anomalies at the moment a QF-PCR, SNP array, and/or gene panel analyses and/or trio WES can be performed.

 

While prenatal genetic testing can be rather complex, for example by revealing (extremely) rare diagnoses with variable phenotypes or unsolicited findings, prenatal counselling should be performed in specialized centres.

 

Strategy interpretation genetic test results:

A Dutch inventory shows that DNA testing often reveals variants of uncertain (or unknown) significance (unpublised data).

While classification of a gene variant of unkown significance (VUS) requires integrated analyses of genetic, complete phenotypic and clinical data (including pedigree), it is important VUS –es with uncertain classification are discussed by the laboratory specialist and clinical geneticist together. In addition, clinical imput by other medical experts (e.g. gynaecologist, plastic surgeon and paediatrician) and embryologist can be valuable to interprete a variant of unknown significance (VUS).

It is important to inform the laboratory about the eventual conclusion and genetic diagnosis of the patient after follow-up. These data are of great importance for classifying variants in future patients.

 

A national cleft working group bringing together a multidisciplinary panel of clinical cleft experts (including clinical geneticists, laboratory specialists, plastic surgeons, paediatricians and embryologists) from different expert centres would promote development of specific cleft expertise. Discussing identified genevariants with uncertain pathogenicity, complex patients and novel research knowledge in a regular meeting (every quarter) would expand current knowledge.

 

Strategy data sharing:

Development of a biobank containing complete cleft data of the dutch population, including genetic and phenotypic data, will help to identify phenotype-genotype correlations and determine pathogenicity of variants of unknown significance (VUS-ses).

It would be desirable to have a national database containing both phenotypic (subclassification) and genetic data (including pathogenic variants as well as variants of unclear significance (VUS)) of CLA/P patients in the Netherlands. The possibility to connect to current national databases of the NVSCA and ICHOM – International Consortium for Health Outcome Measurement) could be explored.

 

Although, privacy issues and government rules might be limiting factors in implementation of such a database.

 

Innovation genepanel analysis:

It is also noted that increasing knowledge urge a regular update of the gene panels. Certain genetic causes of clefting can be missed because novel cleft genes are not yet included in the gene panel.

 

Cost-effectiveness:

For now, the actual benefit and cost-effectiveness of genetic testing cannot be determined until the yield of genetic testing has been investigated in an unbiased population, and follow-up studies have been performed to analyse the effect of a specific diagnosis, considering the quality of life of people with CLA/P and their parents.

Onderbouwing

With the advance of prenatal ultrasound screening genetic testing for CLA/P has shifted more and more from postnal to prenatal testing and counseling. At the same time technologic developments have diminished the differences between genetic tests available prenatally and post postnatally. So taken from a genetic testing point of view the differences between prenatal and postnatal testing are vanishing. Therefore, the working group decided to keep all the information in one module instead of splitting in pre- and postnatal testing. In the literature review, rationale and and recommendations about genetic testing the results are applicable in the prenatal and postnatal setting unless specified otherwise.

 

A cleft of the lip, alveolus and/or palate (CLA/Ps) is a congenital abnormality with a complex etiology and a broad spectrum of causes consisting of - among other factors - chromosomal abnormalities, several gene mutations, teratogens, nutritional deficiencies and infections during pregnancy (Dixon, 2011; Leslie, 2013; Conte, 2016).

 

CLA/P is often an isolated condition but can be associated with multiple congenital anomalies, development delay and/or be part of a syndromic diagnosis. More than 275 syndromes have been described in which CLA/P is a characteristic symptom (Setó-Salvia, 2014). Depending on the underlying cause, monitoring for specific features might be required. (Maarse, 2012; Setó-Salvia, 2014).

 

Therefore, recognition of a syndromic/genetic cause for the cleft is important for tailored and personalized care and long-term management, but also crucial for accurate genetic counselling. The recurrence risk for non-syndromic and syndromic cleft can differ considerably.

 

However, it might be difficult to distinguish syndromic and non-syndromic CLA/Ps. Prenatally, certain syndromic features (e.g. lippits in Van der Woude syndrome) can not be detected by ultrasound. After birth, minor syndromic features can also be hard to recognize (e.g. distichiasis in Lymphedema-distichiasis syndrome), or only appear at a later stage (e.g. myopia in Stickler syndrome, Lymphedema-distichiasis syndrome (Rozendaal, 2012, Setó-Salvia, 2014). Furthermore, cleft syndromes can be associated with reduced penetrance.

 

Rittler (2011) reported that 7 to 9 % of the children with CLA/P that are initially thought to be isolated cases are found to have associated abnormalities. Furthermore, various known “syndromic” CLA/P genes can also be responsible for non-syndromic CLA/P, demonstrating isolated and syndromic clefting can be part of an overarching spectrum (Jezewski, 2003; Leoyklang, 2006; Leslie, 2015a and b, Moreno, 2009; Rahimov, 2012, Setó-Salvia, 2014, Brito, 2015).

 

In 2021, there are various options avaialbe for genetic testing to obtain a diagnosis, including targeted gene testing, gene panel analysis, Whole Exome (and Genome) Sequencing and CNV analysis and in specific cases methylation assays and RNA analysis.

 

However, the optimum strategy for genetic testing, considering the yield of genetic testing, clinical impact, effect on treatment outcomes and benefit for patients and parents, still must be determined.

A systematic review of the literature was performed to answer the following question:

What is the effect of different genetic tests in isolated clefts of the lip and/or palate on the diagnostic yield in isolated clefts of the lip and/or palate?

 

P: patients with isolated cleft lip, alveolus, and/or palate or pregnant women undergoing additional testing for suspected cleft lip, alveolus, and/or palate in their child;

I: diagnostic genetic tests (copy number variant (CNV) analysis (e.g. array comparative genomic hybridization (CGH), SNP array, CMA), next generation sequencing, e.g. gene panels, whole exome sequencing);

C: comparison of the tests above;

R: long term follow-up of children with apparently isolated cleft to identify late onset features an underlying genetic/ syndrome diagnose;

O: yield, sensitivity, specificity, diagnostic accurateness.

 

Relevant outcome measures

The working group considered yield as a critical outcome measure for decision making. The yield of a diagnostic test is defined as the ability to identify underlying genetic variants as cause of CLA/P. Sensitivity, specificity, and diagnostic accurateness were considered as important outcome measures for decision making. The working group considered a sensitivity or specificity above 80% as sufficient.

 

Search and select (Methods)

The previous module on genetic testing in the 2018 edition of the guideline was based on expert opinion and did not provide a systematic search. The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 13th of February 2020. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 165 hits. Studies were selected based on the following criteria: patient population consisting of children (< 18 years) with CLA/P (both syndromic and non-syndromic) and first-degree relatives (parents or siblings), or pregnant women of a child with possible CLA/Ps. The intervention was a diagnostic genetic test: copy number variant (CNV) analysis (for example array comparative genomic hybridization (CGH), SNP array, CMA), next generation sequencing, e.g. gene panels, whole exome sequencing). Eight studies were initially selected based on title and abstract screening. After reading the full text, these eight studies were excluded since they did not compare diagnostic tests (see the table with reasons for exclusion under the tab Methods). Thus, no studies were selected for the literature summary.

 

Results

No studies were found that compared the yield and benefit of the genetic test and provided insight into the total yield, sensitivity, specificity, and diagnostic accurateness of these different tests.

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  2. Aref-Eshghi E, Kerkhof J, Pedro VP et al. (2020). Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders. Am J Hum Genet;106(3):356-370.
  3. Brito LA, Yamamoto GL, Melo S et al (2015). Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate. Hum Mutat;36(11):1029-33.
  4. Bureau, A., Parker, M.M., Ruczinski, I., e al. (2014). Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts. Genetics; 197, 1039–1044.
  5. Basha, M., Demeer, B., Revencu, N. et al. (2018). Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/ or palate in genes mutated in well-known syndromes. J Med Genet;55:449–458.
  6. Beaty TH, Taub MA, Scott AF et al. (2013). Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. I.Hum Genet;132(7):771-81
  7. Cao Y., Li, Z., Rosenfeld, J.A. et al. (2016). Contribution of genomic copy-number variations in prenatal oral clefts: a multicenter cohort study. Genetics in medicine; 10; 1052-1055.
  8. Conte F., Oti, M., Dixon, J. et al. (2016). Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts. Hum Genet; 135:41–59.
  9. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011;12(3):167-178.
  10. Jezewski PA, Vieira AR, Nishimura C et al (2003). Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet. 2003;40(6):399-407.
  11. Jugessur A, Shi M, Gjessing HK et al. (2009). Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia PLoS One;4(4):e5385
  12. Leoyklang P, Siriwan P, Shotelersuk (2006). A mutation of the p63 gene in non-syndromic cleft lip..J Med Genet. 2006
  13. Leslie EJ, Taub MA, Liu H et al (2015). Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. Am J Hum Genet;96(3):397-411.
  14. Ludwig KU, Mangold E, Herms S et al. (2012). Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet;44(9):968-71.
  15. Maarse, W., Rozendaal, A.M., Pajkrt, E., Vermeij-Keers, C., Mink van der Molen, A.B., van den Boogaard, M.J.H. (2012). A systematic review of associated structural and chromosomal defects in oral clefts: when is prenatal genetic analysis indicated? J Med Genet;49:490–498.
  16. Moreno LM, Mansilla MA, Bullard SA et al. (2009), FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Hum Mol Genet; 15;18(24):4879-96.
  17. Rahimov F, Jugessur A, Murray JC (2012). Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J;49(1):73-91.
  18. Rittler M, Cosentino V, López-Camelo JS et al (2011). Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up. Am J Med Genet A. 2011;155A(7):1588-96.
  19. Rozendaal AM, Luijsterburg AJ, Ongkosuwito EM, et al (2012). Delayed diagnosis and underreporting of congenital anomalies associated with oral clefts in the Netherlands: a national validation study. J Plast Reconstr Aesthet Surg;65(6):780-90.
  20. Setó-Salvia, N, Stanier, P (2014). Genetics of cleft lip and/or cleft palate: association with other common anomalies. Eur J Med Genet.;57(8):381-93.
  21. Szczaluba, K., Nowakowska, B.A., Sobecka, K. et al. (2015). High-Resolution Array Comparative Genomic Hybridization Utility in Polish Newborns with Isolated Cleft Lip and Palate. Neonatology;107:173–178.
  22. van der Veen FJ, van Hagen JM, Berkhof J, Don Griot JP. (2006). Regional underreporting of associated congenital anomalies in cleft patients in the Netherlands. Cleft Palate Craniofac J.Nov;43(6):710-4.

Table of excluded studies

Author and year

Reason for exclusion

Lansdon, 2018

Did not provide insight into the value of the array technique for clinical practice

Mouthon, 2019

Article is about micrognathia instead of CLA/P.

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 26-11-2021

Laatst geautoriseerd  : 26-11-2021

The Board of the Dutch Society for Plastic and Reconstructive Surgery (NVPC) will assess whether this guideline module is still up-to-date in 2026 at the latest. If necessary, a new working groupwill be appointed to revise the guideline module. The validity of the guideline or modules of the guideline may lapse earlier when new developments arise. As the holder of this guideline, the NVPC is chiefly responsible for keeping the guideline up to date.

 

Module1

Responsible party2

Year of autorisation

Next assessment of actuality guideline3

Frequency of assessement of actuality4

Supervisor of actuality5

Relevant factors for changes in recommendations6

Diagnostic genetic testing

NVPC

2021

2026

every 5 years

NVPC

None

[1] Name of module

2 Responsible party for the module

3 maximum of 5 years

4 half a year, every (other,..) year

5 supervising party or parties

6 Current reseach, changes in organizations/restitions, new available rescourses

 

Other scientific organizations participating in the guideline or users of the guideline share the responsibility to inform the chiefly responsible party (NVPC) about relevant developments within their fields.

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging voor Plastische Chirurgie
Geautoriseerd door:
  • Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
  • Nederlandse Vereniging voor Kindergeneeskunde
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Plastische Chirurgie
  • Vereniging Klinische Genetica Nederland
  • Nederlands Instituut van Psychologen
  • Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
  • Nederlandse Verenging voor Schisis en Cranio Faciale Afwijkingen
  • Nederlandse Vereniging van Orthodontisten

Algemene gegevens

The revision of this guideline module was supported by Knowledge Institute Federation of Medical Specialists (https://www.demedischspecialist.nl/kennisinstituut) and was financed by the Quality Foundation of the Dutch Medical Specialists (SKMS). The funding organization did not have any influence on the content of the guideline in any way.

Doel en doelgroep

Objectives of the guideline

The aim of this guideline is to improve the care of children/patients with CLA/Ps in The Netherlands ranging from prenatal detection to young adulthood, substantiated by scientific knowledge from research where possible. ‘Improving’ also means providing insight in the differences in practices between cleft teams and discriminating between wanted and unwanted (i.e. scientifically based or non-scientifically based) practice variation. This resulted in recommentations for a more uniform treatment. However, the lack of high-quality studies and evidence remains a serious limiting factor and forced the working group to define some conclusions in a more generalized way than was wished for at the start.

 

Specific attention will be given to the following aspects:

  1. reducing undesirable/unfounded practice variation in the working method and treatment protocols of the Dutch cleft teams, without hampering custom work, innovation or research;
  2. making objective / evidence-based information about the treatment of CLA/Ps available and accessible to healthcare providers, patients, parents and other parties;
  3. determine to what extent the existing organisation of care needs to be changed in order to meet the requirements regarding “state of the art” treatment of a child or adult with CLA/Psand the follow-up to this treatment.

 

In this manner, the guideline offers a tool to create more uniform care in the field of the prenatal and postnatal treatment of a child with CLA/Ps and the implementation of this care in the Netherlands.

 

Intended users of the guideline

The guideline is primarily intended for all healthcare professionals who are involved in caring for a child with CLA/Ps: general practitioners, midwives, gynaecologists, paediatricians, ENT physicians, plastic surgeons, maxillofacial surgeons, orthodontists, clinical geneticists, specialised nurses, speech therapists, (paediatric) dentists, medical psychologists, remedial educationalists and social workers. The secondary target group involves patients, parents and their surroundings.

Samenstelling werkgroep

A multidisciplinary working group was appointed by the Dutch Society for Plastic and Reconstructive Surgery in October 2019 to update the existing guidelines for clefts of the lip and palate. The original guidelines were initiated by the Dutch Society for Plastic and Reconstructive Surgery and this Society remains responsible for the revisions. The working group subsequently updated both the guideline for prenatal counsellling for clefts of the lip, alveolus, and/or palate (Counseling na prenataal vastgestelde schisis, 2011) and postnatal treatment (Behandeling van patiënten met een schisis, 2018). The working group consisted of representatives from all relevant specialties involved in the care for patients with cleft lip, alveolus and/or palate. Members were mandated by their professional organizations. The working group consisted of a mix of new members and members, who worked on previous editions as well. The group worked on the update of the guideline for two years. The working group is responsible for the full text of this guideline.

 

Working group

  • Dr. A.B. Mink van der Molen, MD, plastic surgeon, Universitair Medisch Centrum Utrecht, (chairman), NVPC
  • Dr. M.F. van Dooren, clinical geneticist, Erasmus MC Rotterdam, VKGN
  • Dr. M.J.H. van den Boogaard, clinical geneticist, Universitair Medisch Centrum Utrecht, VKGN
  • Dr. L.N.A. van Adrichem, MD, plastic surgeon, Universitair Medisch Centrum Utrecht, NVPC
  • Dr. H.F.N. Swanenburg de Veye, psychologist, Universitair Medisch Centrum Utrecht/Wilhelmina Kinderziekenhuis, Utrecht, NIP
  • Dr. C.J. Bax, MD, gynaecologist, Amsterdam UMC, NVOG
  • Prof. dr. C.C. Breugem, MD, plastic surgeon, Amsterdam Medical Center and Meander Medical Center, NVSCA
  • Drs. F. Bierenbroodspot, MD, Oral and maxillofacial surgeon, Isala, Zwolle, NVMKA
  • Drs. M. Haasnoot, MD, paediatrician, Wilhelmina Kinderziekenhuis, Utrecht, NVK
  • Drs. H.H.W. de Gier, MD, otolaryngologist, Erasmus MC Rotterdam, NVKNO
  • Dr. M.A.R Kuijpers, orthodontist, Radboud University Medical Center, NVvO
  • Dr. M.E.L. Nienhuijs, MD, Oral and maxillofacial surgeon, Radboud University Medical Center, NVSCA
  • Dr. D. de Haan, patient representative, Schisis Nederland

 

Advisory board

  • Drs. B. Spaan, dentist, CBT Vogellanden Zwolle, NVvK
  • I. Noureldin - Hop, orthopedagogue, NSDSK, NVO
  • M. J. Coerts, speech therapist, Amsterdam UMC, NVLF

 

With methodological support of

  • Drs. A.A. Lamberts, senior advisor, Knowledge Institute Federation of Medical Specialists
  • Dr. M. den Ouden - Vierwind, advisor, Knowledge Institute Federation of Medical Specialists

Belangenverklaringen

According to the KNMG-code, all members of the working group have declared in writing if, in the last five years, they have held a financially supported position with commercial businesses, organisations or institutions that may have a connection with the subject of the guidelines. Enquiries have also been made into personal financial interests, interests pertaining to personal relationships, interests pertaining to reputation management, interests pertaining to externally financed research, and interests pertaining to valorisation of knowledge. These Declarations of Interest can be requested from the secretariat of the Knowledge Institute of Medical Specialists. See below for an overview.

 

Member

Profession

Side jobs

Declared conflicting interests

Actions

Dr. A.B. Mink van der Molen

plastic surgeon,

None

None

No actions

Dr. M.F. van Dooren

clinical geneticist

Co-chair VKGN

None

No actions

Dr. M.J.H. van den Boogaard

clinical geneticist

None

None

No actions

Dr. L.N.A. van Adrichem

plastic surgeon

DGA van Adrichem Medical B.V.

Chairman Concilium plastico chirurgicum

Member Raad Opleiding

Member BBC NVPC

Advisor Hoofdmaatje

Chairman Medical Council Equipe Zorgbedrijven

Member Medicatie Commissie Equipe Zorgbedrijven

Member stuurgroep STW project TU-Twente

None

No actions

Dr. H.F.N. Swanenburg de Veye

psychologist

None

None

No actions

Dr. C.J. Bax

gynaecologist

Volunteer hospice

Member NIPT consortium

Member committee quality documents NVOG

Secretary committee Otterlo NVOG

Treasurer working group infectious diseases NVOG

None

No actions

Dr. C.C. Breugem

plastic surgeon

None

None

No actions

Drs. F. Bierenbroodspot

Oral and maxillofacial surgeon

Working Group Esthetische Aangezichtschirurgie

None

No actions

Drs. M. Haasnoot

paediatrician

None

None

No actions

Dr. J. de Gier

otolaryngologist

Board member NVSCA

None

No actions

Dr. M. Kuijpers

orthodontist

Guideline committee Mondzorg voor jeugdigen preventie diagnostiek behandeling

None

No actions

Dr. M. Nienhuijs

Oral and maxillofacial surgeon

Boardmember NVSCA

None

No actions

Dr. D. de Haan

patient representative,

Teacher/ education advisor HU-PABO, Hogeschool Utrecht

None

No actions

Inbreng patiëntenperspectief

Patients were represented by Schisis Nederland. Schisis Nederland is an independent organization representing patients with CLA/Psand their parents in the Netherlands. Representatives from Schisis Nederland participated in the working group. The concept guideline module was presented to Schisis Nederland for their comments.

 

Qualitative estimation of possible financial impact under the Wkkgz / Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

In accordance with the Wet kwaliteit, klachten en geschillen zorg (Wkkgz), a qualitative estimation has been made whether the recommendations in the guideline may lead to substantial financial consequences. In carrying out this assessment, guideline modules were tested in various domains (see the flow chart).

The qualitative estimate shows that there is probably no substantial financial impact, see table below.

 

Module

Results qualitative estimation

Elucidation

Module Genetische diagnostiek bij schisis

Likely no substantial financial impact

The recommendation(s) are not widely applicable (<5,000 patients) and are therefore expected to have no substantial financial consequences for public expenditure.

Methode ontwikkeling

Evidence based

Implementatie

Guideline implementation and practical applicability of the recommendations was taken into consideration during various stages of guideline development. Factors that may promote or hinder implementation of the guideline in daily practice were given specific attention. The guideline is distributed digitally among all relevant professional groups. The guideline can also be downloaded from the Dutch Society for Plastic and Reconstructive Surgery website: www.nvpc.nl, and the guideline website: www.richtlijnendatabase.nl. The implementation table can be found in the related products.

Werkwijze

AGREE

The guideline has been drafted in accordance with the requirements outlined in the ‘Guidelines 2.0’ report of the Guideline Advisory Committee of the Council on Science, Education and Quality (WOK). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (Brouwers, 2010), an instrument designed to assess the quality of guidelines with broad international support (Brouwers, 2010). The development of a evidence-based guideline module is described step-by-step in “Ontwikkeling van Medisch Specialistische Richtlijnen” of Knowledge Institute for Medical Specialists.

 

Inventory of the problem areas

During the preparation phase the working group used an inventory to find the problem areas. A report of this inventory can be found in the related products.

 

Primary questions and outcome measures

Based on the outcomes of the bottleneck analysis, the president and advisor formulated draft primary questions. These were discussed and defined together with the working group. Subsequently, the working groupdetermined which outcome measures were relevant for the patient for each primary question, examining both desired and undesirable effects. The working groupvaluated these outcomes based on their relative importance as crucial, important and unimportant.

 

Literature search and selection strategy

Specific search terms were used to identify published scientific studies related to each individual primary question in electronic databases like Medline, Cochrane, and Embase. Additionally, the references of the selected articles were screened for additional relevant studies. Studies offering the highest level of evidence were sought out first. Members of the working group selected articles identified by the search based on predetermined criteria. Theselected articles were used to answer the primary question. The searched databases, the search string or terms used during the search and selection criteria applied are listed in the module for each individual primary question.

 

Quality assessment of individual studies

Individual studies were assessed systematically based on predefined methodological quality criteria in order to assess the risk of biased study results. These assessments may be found in the column ‘Study quality assessment’ in an evidence table.

  • AMSTAR - for systematic reviews.
  • Cochrane - for randomized controlled trials.
  • ACROBAT-NRS - for observational studies.
  • QUADAS II - for diagnostic studies.

 

Summary of the literature

The relevant study results from all selected articles were presented clearly in evidence tables. The key findings from the literature are described in the literature summary. If studies were sufficiently similar in design, data were also summarized quantitatively (meta-analysis) using Review Manager 5.

 

Assessment of the level of scientific evidence

With regard to intervention questions, the level of scientific evidence was determined using the GRADE method. GRADE is short for ‘Grading Recommendations Assessment, Development and Evaluation’ (see http://www.gradeworkinggroup.org/)

 

GRADE distinguishes four grades of quality of evidence, i.e. high, moderate, low and very low. These grades indicate the degree of confidence in the conclusions in the literature ((Schünemann, 2013; Hultcrantz, 2017).

 

GRADE

Definition

High

  • There is a high degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature.
  • It is very unlikely that the conclusion drawn in the literature will change if further research is done.

Moderate

  • There is a moderate degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature.
  • It is possible that the conclusion drawn in the literature will change if further research is done.

Low

  • There is a limited degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature.
  • It is probable that the conclusion drawn in the literature will change if further research is done.

Very low

  • There is little confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature.
  • The conclusion is very uncertain

 

According to the GRADE methodology the clinical decision threshold should play an important role in assessing the level of evidence (grading) in guidelines (Hultcrantz, 2017). To set the threshold all critical outcomes, and the considerations should be determined. The clinical decision threshold is not exactly the same as the Minimal Clinically Important Difference (MCID). In situations in which an intervention has no important disadvantages and low costs, the clinical decision threshold with regard to the efficiency of an intervention can be lower (closer to zero/ no effect) than MCID (Hultcrantz, 2017).

 

Formulation of conclusions

For interventions, the conclusion does not refer to one or more articles, but is drawn based on the body of evidence. The working group looked at the net benefits of each intervention. This was done by determining the balance between favourable and unfavourable effects for the patient.

 

With regard to questions about the value of diagnostic tests, harm or adverse effects, aetiology and prognosis, the scientific evidence is summarized in one or more conclusions, listing the level of evidence for the most relevant data.

 

Considerations

When making recommendations, scientific evidence was considered together with other key aspects, such as expertise of the group members, patient preferences, costs, availability of facilities and/or organizational aspects. Insofar as they are not part of the systematic literature review, these aspects are listed under ‘Considerations’. The considerations are written using a structured format based on the evidence-to-decision framework of the international GRADE Working Group, and part of the GRADE methodology (Alonso-Coello, 2016a; Alonso-Coello 2016b).

 

Formulation of recommendations

Recommendations provide an answer to the primary question and are based on the best scientific evidence available and the most important considerations. The level of scientific evidence and the importance given to considerations by the working group jointly determine the strength of the recommendation. In accordance with the GRADE method, a low level of evidence for conclusions in the systematic literature review does not rule out a strong recommendation, while a high level of evidence may be accompanied by weak recommendations (Agoritsas, 2017; Neumann, 2016). The strength of the recommendation is always determined by weighing all relevant arguments.

 

Preconditions (Organisation of care)

In the analysis of problem areas, the organisation of care (all those aspects that are preconditions for the provision of care) were explicitly taken into account. These aspects include coordination, communication, materials, financial means, work force and infrastructure. Preconditions that are relevant to the answering of a specific clinical question are part of the considerations related to that specific question.

 

Knowledge gaps

During the development of this guideline, systematic searches were conducted for research contributing to answering the primary questions. For each primary question, the working group determined whether (additional) scientific research is desirable.

 

Commentary and authorization phase

The draft guideline was submitted to the (scientific) organizations involved for comment. The guideline was also submitted to the following organizations for comment: Dutch College of General Practitioners (NHG), Healthcare Insurers Netherlands (ZN), The Dutch Healthcare Authority (NZA), the National Health Care Institute (ZINL), the Health Care Inspectorate (IGJ), Dutch Organisation of Hospitals (NVZ), Dutch Federation of Academic Hospitals (NFU), Dutch Organisation of Independent Clinics (ZKN), the Netherlands Patients Federation, Dutch Organisation of nurses and caregivers (V&VN), Dutch Association of Physician Assistants, and Collaborating Top Clinical Training Hospitals (STZ). Comments were collected and discussed with the working group. The draft guideline was updated and finalized by the working group based on the comments. The final guideline was submitted for authorization to the (scientific) organizations involved and authorized or approved by them.

 

Literature

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348.

Hultcrantz M, Rind D, Akl EA, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. doi: 10.1136/bmj.39500.677199.AE. Erratum in: BMJ. 2008;336(7654). doi: 10.1136/bmj.a139. PubMed PMID: 18483053.

Wessels M, Hielkema L, van der Weijden T. How to identify existing literature on patients' knowledge, views, and values: the development of a validated search filter. J Med Libr Assoc. 2016 Oct;104(4):320-324. PubMed PMID: 27822157; PubMed Central PMCID: PMC5079497.

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