What If Craniosynostosis Genetic Testing Is Negative?
At a Glance
A negative genetic test for syndromic craniosynostosis does not mean your child does not have a syndrome. It only means the specific test used didn't find a known mutation. Doctors often rely on clinical diagnosis based on physical features and may recommend broader tests like Whole Exome Sequencing.
If your child’s genetic test for syndromic craniosynostosis comes back negative, it does not necessarily mean they do not have a syndrome. A negative result simply means that the specific test performed did not find a known, disease-causing genetic change based on our current scientific understanding [1][2]. Many children receive a clinical diagnosis based on their physical features and medical history even when genetic testing cannot pinpoint the exact cause [1].
Why Genetic Tests Can Be “Negative”
The genetic causes of syndromic craniosynostosis are incredibly diverse (heterogeneous), meaning many different genes can be involved [3]. There are several reasons why a genetic test might not provide a clear answer even if a child has a syndrome:
- Undiscovered Genes: Medical science has not yet discovered every gene responsible for craniosynostosis syndromes [4]. New genes, such as CDC45 (associated with features like craniosynostosis, facial dysmorphism, and brachydactyly), are being identified as research progresses [5][6].
- Variants of Uncertain Significance (VUS): Sometimes the lab finds a genetic change, especially a new or de novo mutation (a random change not inherited from either parent), but there isn’t enough medical evidence yet to know if it actually causes the syndrome [7][8]. This is reported as a “Variant of Uncertain Significance” (VUS) rather than a strict positive or negative, leaving parents with an uncertain result [9]. Over time, a VUS may be reclassified as more research becomes available [10].
- Limitations of Standard Panels: Standard genetic panels only look at a curated list of known genes [2]. If the mutation is in a newly discovered gene or a gene not included on that specific panel, the test will simply miss it [6][11].
- Complex Genetic Changes: Some genetic variations—like structural variants or complex rearrangements of chromosomes—can disrupt how genes function but are difficult to detect using standard sequencing methods [12][13].
The Diagnostic Odyssey and Next Steps
When an initial genetic test is negative, it can lead to what is known as a “diagnostic odyssey”—a frustrating and sometimes isolating period of searching for answers. Organizations like SWAN (Syndromes Without A Name) exist to provide emotional support and community for families navigating an undiagnosed condition.
There are practical next steps you can take with your medical team. If your child only had a standard targeted panel, the next step may be to ask about upgrading to broader genomic testing [6]:
- Whole Exome Sequencing (WES): Looks at all the protein-coding genes in the body, rather than just a short list [5].
- Whole Genome Sequencing (WGS): Looks at nearly the entire genetic code, including the spaces between genes that regulate how they work.
Because our understanding of genetics is constantly expanding, researchers are continually finding new links between genes and conditions like craniosynostosis [14][15]. If your child has already had WES or WGS, the raw data from those tests is usually stored. Studies show that periodically reanalyzing this data every one to two years can sometimes uncover a diagnosis that was missed initially, simply because the gene is newly recognized [16][17][18].
A thorough clinical evaluation by your geneticist and craniofacial team remains the most critical tool for diagnosing and managing your child’s care, regardless of the genetic test results [2]. They will continue to treat the symptoms and monitor your child’s development based on their unique needs.
Common questions in this guide
Does a negative genetic test mean my child doesn't have a craniosynostosis syndrome?
What is a Variant of Uncertain Significance (VUS) on a genetic report?
What are the next steps if standard genetic testing for craniosynostosis is negative?
Should old genetic test data for craniosynostosis be reanalyzed?
Questions to Ask Your Doctor
Curated prompts to bring to your next appointment.
- 1.Was my child's test a standard panel or broader testing like Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS)?
- 2.Did the genetic report identify any 'Variants of Uncertain Significance' (VUS)?
- 3.If we have WES or WGS data on file, what is your clinic's protocol for periodically reanalyzing the data, and when is our next review date?
- 4.How does not having a confirmed genetic diagnosis change your approach to monitoring and treating my child's craniosynostosis and other features?
Questions For You
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Related questions
References
References (18)
- 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
Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the TWIST1 and EFNB1 Genes.
Apostolopoulou D, Kaxira OS, Hatzaki A, et al.
The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 2018; (55(8)):1092-1102 doi:10.1177/1055665618760412.
PMID: 29561715 - 3
Syndromic Craniosynostosis: A Comprehensive Review.
Katouni K, Nikolaou A, Mariolis T, et al.
Cureus 2023; (15(12)):e50448 doi:10.7759/cureus.50448.
PMID: 38222144 - 4
Whole-exome sequencing identifies a de novo PDE3A variant causing autosomal dominant hypertension with brachydactyly type E syndrome: a case report.
Li X, Li Z, Chen P, et al.
BMC medical genetics 2020; (21(1)):144 doi:10.1186/s12881-020-01077-z.
PMID: 32631253 - 5
Prenatal diagnosis of Meier-Gorlin syndrome 7: a case presentation.
Li X, Zhang LZ, Yu L, et al.
BMC pregnancy and childbirth 2021; (21(1)):381 doi:10.1186/s12884-021-03868-5.
PMID: 34000999 - 6
Familial monoallelic CYP26B1 truncating variant causes a syndromic craniosynostosis due to haploinsufficiency ?
Sarma AS, Peter Mathew R, Dalal A, et al.
European journal of medical genetics 2023; (66(7)):104772 doi:10.1016/j.ejmg.2023.104772.
PMID: 37100236 - 7
Genetic Syndromes Associated with Craniosynostosis.
Ko JM
Journal of Korean Neurosurgical Society 2016; (59(3)):187-91 doi:10.3340/jkns.2016.59.3.187.
PMID: 27226847 - 8
The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change.
Rehm HL, Alaimo JT, Aradhya S, et al.
Genetics in medicine : official journal of the American College of Medical Genetics 2023; (25(12)):100947 doi:10.1016/j.gim.2023.100947.
PMID: 37534744 - 9
Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study.
Adam F, Fluri M, Scherz A, Rabaglio M
BMC medical genomics 2023; (16(1)):7 doi:10.1186/s12920-023-01437-7.
PMID: 36647026 - 10
Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care.
Chiang J, Chia TH, Yuen J, et al.
JCO precision oncology 2021; (5()):577-584 doi:10.1200/PO.20.00399.
PMID: 34994607 - 11
AXIN1 mutations in nonsyndromic craniosynostosis.
Timberlake AT, Hemal K, Gustafson JA, et al.
Journal of neurosurgery. Pediatrics 2024; (34(3)):246-251 doi:10.3171/2024.5.PEDS24115.
PMID: 38905707 - 12
Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism.
Li D, Strong A, Hou C, et al.
Molecular cytogenetics 2022; (15(1)):33 doi:10.1186/s13039-022-00610-4.
PMID: 35932041 - 13
Structural Genome Variations Related to Craniosynostosis.
Poot M
Molecular syndromology 2019; (10(1-2)):24-39 doi:10.1159/000490480.
PMID: 30976277 - 14
Syndromic craniosynostosis caused by a novel missense variant in MAP4K4: Expanding the genotype-phenotype relationship in RASopathies.
Yoon JG, Yu JW, Shim KW, et al.
Clinical genetics 2024; (106(2)):199-203 doi:10.1111/cge.14539.
PMID: 38679877 - 15
Dissection of contiguous gene effects for deletions around ERF on chromosome 19.
Calpena E, McGowan SJ, Blanco Kelly F, et al.
Human mutation 2021; (42(7)):811-817 doi:10.1002/humu.24213.
PMID: 33993607 - 16
Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.
Rochtus A, Olson HE, Smith L, et al.
Epilepsia 2020; (61(2)):249-258 doi:10.1111/epi.16427.
PMID: 31957018 - 17
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 - 18
Genetics of mitochondrial diseases: Identifying mutations to help diagnosis.
Stenton SL, Prokisch H
EBioMedicine 2020; (56()):102784 doi:10.1016/j.ebiom.2020.102784.
PMID: 32454403
This page provides educational information about genetic testing for syndromic craniosynostosis. Always consult your child's geneticist or craniofacial team to interpret specific test results and determine next steps.
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