The identification of two pathogenic variants in a family with mild and severe forms of developmental delay

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.

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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.

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Correspondence to Ahmad Reza Salehi Chaleshtori.

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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 (2020). https://doi.org/10.1038/s10038-020-0809-8

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