Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband’s family members might impact exome data interpretation.
Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters and images. If a discrepancy between reported clinical findings and presumably disease-causing variant segregation was observed, referring clinicians were contacted for phenotypic clarification.
In 16/209 (7.7%) cases, phenotypic refinement was important due to (1) lack of cosegregation of disease-causing variant with the reported phenotype; (2) identification of different disorders with overlapping symptoms in the same family; (3) similar features in proband and family members, but molecular cause identified in proband only; and (4) previously unrecognized maternal condition causative of child’s phenotype. As a result of phenotypic clarification, in 12/16 (75%) cases definition of affected versus unaffected status in one of the family members has changed, and in one case variant classification has changed.
Detailed description of phenotypes in family members including differences in clinical presentations, even if subtle, are important in exome interpretation and should be communicated to the variant interpretation team.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wai HA, Lord J, Lyon M, et al. Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. Genet Med. 2020;22:1005–1014.
Cao Y, Tokita MJ, Chen ES, et al. A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. Genome Med. 2019;11:48.
Basel-Salmon L, Orenstein N, Markus-Bustani K, et al. Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested. Genet Med. 2019;21:1443–1451.
Richards S, Aziz N, Bale S, ACMG Laboratory Quality Assurance Committee, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
Bend R, Cohen L, Carter MT, Lyons MJ, et al. Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities. Eur J Hum Genet. 2020;28:76–87.
Tan TY, Sedmík J, Fitzgerald MP, et al. Bi-allelic ADARB1 variants associated with microcephaly, intellectual disability, and seizures. Am J Hum Genet. 2020;106:467–483.
Mak CCY, Doherty D, Lin AE, et al. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis. Brain. 2020;143:55–68.
Li L, Ghorbani M, Weisz-Hubshman M, et al. Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability. J Clin Invest. 2020;130:1431–1445.
Horn S, Au M, Basel-Salmon L, et al. De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures. Brain. 2019;142:3351–3359.
Magini P, Smits DJ, Vandervore L, et al. Loss of SMPD4 causes a developmental disorder characterized by microcephaly and congenital arthrogryposis. Am J Hum Genet. 2019;105:689–705.
Orenstein N, Goldberg-Stern H, Straussberg R, et al. A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder. Eur J Paediatr Neurol. 2018;22:516–524.
Weisz Hubshman M, Broekman S, van Wijk E, et al. Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa. Hum Mol Genet. 2018;27:614–624.
Tropeano M, Ahn JW, Dobson RJ, et al. Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One. 2013;8:e61365.
Brancati F, Sarkozy A, Dallapiccola B. KBG syndrome. Orphanet J Rare Dis. 2006;1:50.
Posey JE, Harel T, Liu P, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21–31.
Waseem NH, Vaclavik V, Webster A, Jenkins SA, Bird AC, Bhattacharya SS. Mutations in the gene coding for the pre-mRNA splicing factor, PRPF31, in patients with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2007;48:1330–1334.
Rice GI, Kasher PR, Forte GM, et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243–1248.
Guo H, Bettella E, Marcogliese PC, et al. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nat Commun. 2019;10:4679.
Dulovic-Mahlow M, Trinh J, Kandaswamy KK, et al. De novo variants in TAOK1 cause neurodevelopmental disorders. Am J Hum Genet. 2019;105:213–220.
The manuscript was edited by Debby Mir.
CG-J and ARS are full-time employees of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receive stock options as part of compensation. The remaining authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Basel-Salmon, L., Ruhrman-Shahar, N., Orenstein, N. et al. When phenotype does not match genotype: importance of “real-time” refining of phenotypic information for exome data interpretation. Genet Med (2020). https://doi.org/10.1038/s41436-020-00938-5
- variant interpretation
- phenotypic information
- variant classification
- overlapping features