What Genetic Tests for Craniosynostosis & Brachydactyly?
At a Glance
Children with craniosynostosis and short fingers often need comprehensive genetic testing to find the exact cause. If initial microarrays or gene panels are normal, Trio Whole Exome Sequencing (WES) is highly recommended to identify rare or spontaneous genetic changes missed by earlier tests.
In this answer
5 sections
When a child is born with craniosynostosis (early fusion of skull bones) and short fingers or toes (brachydactyly), doctors will often suspect an underlying genetic condition. Because many different genes can cause this combination of features, pinpointing the exact genetic cause is crucial for understanding your child’s health needs. It can be incredibly frustrating and scary to receive a “normal” or negative result on your child’s first genetic test when you can physically see these differences. However, if initial tests come back negative, deeper and more comprehensive testing is usually the next step [1].
The Starting Point: Chromosomal Microarray (CMA)
Often, the first test doctors order is a Chromosomal Microarray (CMA) [2]. This test looks for extra or missing pieces of chromosomes—large chunks of DNA. While CMA is an excellent first-tier tool [3], it cannot read the individual “letters” of the genes. If a condition is caused by a tiny spelling mistake in a single gene (which is common in syndromic craniosynostosis), the CMA will come back normal [4].
Targeted Gene Panels
In some cases, before moving to broader testing, your doctor might order a Multi-Gene Panel [5]. This test looks only at a specific list of genes known to cause craniosynostosis and skeletal differences [6]. A panel can be a faster and sometimes more affordable option, and it might be required by your insurance before they approve more extensive testing [7]. However, if the panel comes back negative, broader testing is the recommended next step [8].
The Broader Look: Whole Exome Sequencing (WES)
If the microarray or panel is negative, the next critical step is Whole Exome Sequencing (WES) [9]. The “exome” is the part of your DNA that provides the instructions for making proteins. WES is powerful because it reads through all of these instruction-coding genes at once [10], looking for many of the exact spelling mistakes that a microarray misses.
There are over 60 different genes known to cause forms of syndromic craniosynostosis [5]. Some common ones involve the FGFR genes [11], but craniosynostosis combined with brachydactyly can also be caused by rarer genes, such as SLC25A24 [12] (associated with Gorlin-Chaudhry-Moss or Fontaine progeroid syndrome [13]), RSPRY1 [14], or MAP3K20 [15]. Because the list of possible genes is long, looking at a broad range of genes through WES is highly effective for finding answers that targeted panels might miss [16][17].
The Power of Trio Sequencing
When WES is ordered, geneticists highly recommend Trio Sequencing (also called Trio-WES) [18]. This involves testing your child (usually via blood draw or cheek swab), along with both biological parents, at the same time [19].
Comparing the child’s DNA side-by-side with the parents’ DNA helps the lab filter out normal genetic variations [20]. Most importantly, trio sequencing makes it easier to spot a de novo mutation—a new genetic change that happened for the first time in the child and wasn’t inherited from either parent [21][12]. Many syndromes involving craniosynostosis and brachydactyly are caused by these spontaneous de novo changes [22].
What to Expect from the Results
Waiting for genetic results is agonizing. Because WES is highly specialized, results often take several weeks to a few months to return. When they do, the outcome is rarely a simple “yes” or “no.” You might receive one of three outcomes:
- Positive/Pathogenic: A genetic change is found that definitely explains your child’s condition.
- Variant of Uncertain Significance (VUS): A genetic change was found, but doctors are not yet sure if it is a normal, harmless variation or the cause of the disease. Finding a VUS is extremely common in WES and can be frustrating, but your geneticist will help monitor research updates over time.
- Negative: No identifiable changes were found in the exome. If WES is negative, your doctor might recommend Whole Genome Sequencing (WGS), which looks at the entirety of the DNA, not just the exome, and can catch changes that WES misses [23][24].
Common questions in this guide
Why does my child need Whole Exome Sequencing (WES) if the microarray was normal?
What is trio sequencing for craniosynostosis?
What happens if my child's genetic test shows a Variant of Uncertain Significance (VUS)?
Can genetic testing find the cause of both craniosynostosis and short fingers?
Questions to Ask Your Doctor
Curated prompts to bring to your next appointment.
- 1.Does our insurance require us to do a targeted multi-gene panel before they will cover Whole Exome Sequencing (WES)?
- 2.Are we able to do trio sequencing so that both parents can be tested alongside our child?
- 3.If the WES comes back with a Variant of Uncertain Significance (VUS), how do we monitor it for future updates?
- 4.Does the lab you use for WES test for rarer genes linked to brachydactyly, such as SLC25A24 or MAP3K20?
- 5.If all genetic testing, including WES, comes back negative, what is the timeline for considering Whole Genome Sequencing (WGS)?
Questions For You
Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.
Related questions
References
References (24)
- 1
A unique presentation of Crouzon-like syndrome: Complex craniosynostosis in the absence of genetic mutations or familial predisposition - A case report.
Vaja H, Patel SN, Vadher A, et al.
Surgical neurology international 2023; (14()):422 doi:10.25259/SNI_424_2023.
PMID: 38213431 - 2
De Novo Interstitial Deletion of 9q in a Pediatric Patient With Global Developmental Delay.
Keselman D, Singh R, Cohen N, Fefer Z
Child neurology open 2019; (6()):2329048X19844920 doi:10.1177/2329048X19844920.
PMID: 31106228 - 3
Genomic Testing for Diagnosis of Genetic Disorders in Children: Chromosomal Microarray and Next-Generation Sequencing.
Narayanan DL, Girisha KM
Indian pediatrics 2020; (57(6)):549-554.
PMID: 32562398 - 4
Genetic Heterogeneity, Craniofacial Surgical Burden, and Surgical Techniques in Patients With Saethre-Chotzen Syndrome.
Romeo DJ, Oral KT, Massenburg BB, et al.
The Journal of craniofacial surgery 2024; doi:10.1097/SCS.0000000000010348.
PMID: 39058028 - 5
Genetic diagnostic yield in an 11-year cohort of craniosynostosis patients.
Gaillard L, Goverde A, Weerts MJA, et al.
European journal of medical genetics 2023; (66(10)):104843 doi:10.1016/j.ejmg.2023.104843.
PMID: 37716645 - 6
Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.
Hyder Z, Calpena E, Pei Y, et al.
Genetics in medicine : official journal of the American College of Medical Genetics 2021; (23(12)):2360-2368 doi:10.1038/s41436-021-01297-5.
PMID: 34429528 - 7
High diagnostic yield of targeted next-generation sequencing panel as a first-tier molecular test for the patients with myopathy or muscular dystrophy.
Çavdarlı B, Köken ÖY, Satılmış SBA, et al.
Annals of human genetics 2023; (87(3)):104-114 doi:10.1111/ahg.12492.
PMID: 36575883 - 8
Yield of exome sequencing in patients with developmental and epileptic encephalopathies and inconclusive targeted gene panel.
Sedlackova L, Sterbova K, Vlckova M, et al.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2024; (48()):17-29 doi:10.1016/j.ejpn.2023.10.006.
PMID: 38008000 - 9
Diagnostic performance of chromosomal microarray and whole exome sequencing in fetal structural anomalies: a single-center retrospective study.
Özer L, Aktuna S, Ünsal E
BMC pregnancy and childbirth 2025; (25(1)):1029 doi:10.1186/s12884-025-08167-x.
PMID: 41053595 - 10
Exome Sequencing and Its Emerging Role in Prenatal Genetic Diagnosis.
Hopkins MK, Dugoff L, Kuller JA
Obstetrical & gynecological survey 2020; (75(5)):317-320 doi:10.1097/OGX.0000000000000787.
PMID: 32469417 - 11
Clinical study and some molecular features of Mexican patients with syndromic craniosynostosis.
Ibarra-Arce A, Almaraz-Salinas M, Martínez-Rosas V, et al.
Molecular genetics & genomic medicine 2020; (8(8)):e1266 doi:10.1002/mgg3.1266.
PMID: 32510873 - 12
De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.
Ehmke N, Graul-Neumann L, Smorag L, et al.
American journal of human genetics 2017; (101(5)):833-843 doi:10.1016/j.ajhg.2017.09.016.
PMID: 29100093 - 13
Is Gorlin-Chaudhry-Moss syndrome associated with aortopathy?
Legué J, François JHM, van Rijswijk CSP, van Brakel TJ
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2020; (58(3)):654-655 doi:10.1093/ejcts/ezaa108.
PMID: 32355952 - 14
Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis.
Simsek-Kiper PO, Taskiran EZ, Kosukcu C, et al.
American journal of medical genetics. Part A 2018; (176(9)):2009-2016 doi:10.1002/ajmg.a.40427.
PMID: 30063090 - 15
Confirmation of the Hotspot Variant in MAP3K20 Responsible for Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, and Skeletal Anomaly Spectrum.
Taşdelen E, Gönül M, Öztelcan Gündüz B, et al.
Molecular syndromology 2026; (17(3)):255-263 doi:10.1159/000547411.
PMID: 41064052 - 16
Clinical application of whole-exome sequencing analysis in childhood epilepsy.
Gavaz M, Aslan ES, Tekeş S
Journal of neurogenetics 2024; (38(4)):187-194 doi:10.1080/01677063.2024.2434869.
PMID: 39654149 - 17
Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders.
Álvarez-Mora MI, Sánchez A, Rodríguez-Revenga L, et al.
Orphanet journal of rare diseases 2022; (17(1)):60 doi:10.1186/s13023-022-02213-z.
PMID: 35183220 - 18
Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.
Hu X, Guo R, Guo J, et al.
Frontiers in genetics 2020; (11()):473 doi:10.3389/fgene.2020.00473.
PMID: 32595695 - 19
A real-world comparison between the diagnostic yield of trio-whole exome sequencing and proband-only targeted exome sequencing in complex childhood epilepsy.
Fasaludeen A, Jose M, U A, et al.
Seizure 2025; (129()):51-54 doi:10.1016/j.seizure.2025.03.020.
PMID: 40220696 - 20
De Novo Mutation in KRT1 Leads to Epidermolytic Palmoplantar Keratoderma: from Chinese Traditional Treatment to Prenatal Diagnosis Using Whole-Exome Sequencing-Plus.
Ge M, Ji C, Li H, Huang H
DNA and cell biology 2023; (42(10)):645-652 doi:10.1089/dna.2023.0154.
PMID: 37566479 - 21
A head-to-head evaluation of the diagnostic efficacy and costs of trio versus singleton exome sequencing analysis.
Tan TY, Lunke S, Chong B, et al.
European journal of human genetics : EJHG 2019; (27(12)):1791-1799 doi:10.1038/s41431-019-0471-9.
PMID: 31320747 - 22
A rare male patient with Fontaine progeroid syndrome caused by p.R217H de novo mutation in SLC25A24.
Rodríguez-García ME, Cotrina-Vinagre FJ, Cruz-Rojo J, et al.
American journal of medical genetics. Part A 2018; (176(11)):2479-2486 doi:10.1002/ajmg.a.40496.
PMID: 30329211 - 23
Genome Sequencing for Diagnosing Rare Diseases.
Wojcik MH, Lemire G, Berger E, et al.
The New England journal of medicine 2024; (390(21)):1985-1997 doi:10.1056/NEJMoa2314761.
PMID: 38838312 - 24
Genetic Screening of the Patients with Primary Immunodeficiency by Whole-Exome Sequencing.
Erman B, Çipe F
Pediatric allergy, immunology, and pulmonology 2020; (33(1)):19-24 doi:10.1089/ped.2019.1097.
PMID: 33406023
This page explains genetic testing for craniosynostosis and brachydactyly for educational purposes. Always consult a pediatric geneticist to determine the most appropriate diagnostic tests for your child.
Get notified when new evidence is published on Craniosynostosis-dysmorphism-brachydactyly syndrome.
We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.