Abstract
Intellectual disability (ID) accounts for 1% of the general population, and it is caused by the interplay between the genetic and/or environmental factors. The genetic components responsible for the development of ID are highly heterogeneous, and the phenotype and severity of the disease vary in patients even if they have an identical pathological variant and/or belong to the same family. Herein, we reported two male siblings with ID in an Iranian family. By means of the whole-exome sequencing method, elder brother affected by a moderate form of ID exhibited a de novo missense variant in the KCNQ3 gene, while another sibling afflicted with a severe form of the disease exhibited a de novo in-frame deletion in the UBE3A gene. Both variants have been previously ascribed to similar clinical phenotypes. In addition, a genetic variant in the KCNQ3 gene was transmitted to his son, who had a mild form of ID. To our knowledge, all individuals with KCNQ3-related developmental delay show de novo variants in the KCNQ3 gene. Thus, this familial case exhibit milder phenotype that might extend the clinical spectrum of KCNQ3 pathogenic variants. In addition, the current report highlights the significance of the clinical evaluation and non-biased assessment of the genetic analysis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18.
Kubota T, Das S, Christian SL, Baylin SB, Herman JG, Ledbetter DH. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997;16:16–7.
Nicholls RD, Saitoh S, Horsthemke B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 1998;14:194–200.
Iwama K, Osaka H, Ikeda T, Mitsuhashi S, Miyatake S, Takata A, et al. A novel SLC9A1 mutation causes cerebellar ataxia. J Hum Genet. 2018;63:1049–54.
Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, et al. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet. 1999;8:129–35.
Cooper EM, Hudson AW, Amos J, Wagstaff J, Howley PM. Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein. J Biol Chem. 2004;279:41208–17.
Study DDD. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–8.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405–24.
Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012;91:597–607.
Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.
Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, et al. Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutat. 2015;36:1197–204.
Acknowledgements
We should to thank patients and their family members for their participation in the present study. This work was supported by AMED under grant numbers JP20ek0109486, JP18dm0107090, JP20ek0109301, JP20ek0109348, and JP20kk0205012; JSPS KAKENHI grant numbers JP17H01539 and JP19H03621; and intramural grants 30-6 and 30-7 for National Center for Neurology and Psychiatry from the Ministry of Health, Labor and Welfare, and the Takeda Science Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Miyake, N., Heydari, S., Garshasbi, M. et al. The identification of two pathogenic variants in a family with mild and severe forms of developmental delay. J Hum Genet 66, 445–448 (2021). https://doi.org/10.1038/s10038-020-0809-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s10038-020-0809-8