Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings
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Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings Xuemin Zhang 1 & Yajian Wang 2 & Fang Yang 3 & Jiulai Tang 1 & Xiaoyan Xu 1 & Li Yang 1 & Xiu-An Yang 3
&
De Wu 1
Received: 22 April 2019 / Accepted: 29 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract This study presents two Chinese siblings with a rare neurodevelopmental disorder (NDD) caused by biallelic INTS1 mutations and investigates the clinical features of this disease by means of in silico analysis. Two siblings, an 11-yearold brother and a 5-year-old sister, visited our hospital due to physical retardation and profound intellectual disability. Whole-exome sequencing (WES) was performed for the girl, and Sanger sequencing was used to validate the identified variants. Phenotype correlation analysis and in silico genetic interaction network analysis were performed to investigate genes that could lead to diseases similar to the rare disease in the patients. Growth retardation, distinct intellectual disability, hypertelorism, mild cataract, uneven teeth, abnormal palmar and plantar creases, and dubious genitalia were noted in the sister. No neurological features related to neuropathy were found. The brother showed features and growth delay similar to his sister. Heterozygous novel variants of c.1645A>G,p.Met549Val and c.5881C>T,p.Gln1961* in INTS1 were considered a candidate etiology. Sanger sequencing demonstrated that the variants were inherited from the grandfather and (maternal) grandmother. Phenotype correlation analysis revealed that CTDP1 mutation–induced congenital cataracts–facial dysmorphism–neuropathy (CCFDN) mostly overlapped with the performance of our patients. In silico analysis of the genetic interaction network showed that INTS1 is highly associated with INTS8 and CTDP1. Our study further validated that biallelic INTS1 mutations could bring about the onset of a novel neurodevelopmental disorder. Keywords Neurodevelopmental disorder . Whole-exome sequencing . INTS1 . INTS8 . CTDP1 . CCFDN
Introduction
Xuemin Zhang and Yajian Wang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12031-019-01393-x) contains supplementary material, which is available to authorized users. * Xiu-An Yang [email protected] * De Wu [email protected] 1
The Children’s Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Hefei 230022, People’s Republic of China
2
Beijing Chigene Translational Medicine Research Center Co., Ltd., Beijing 100875, People’s Republic of China
3
School of Basic Medical Science, Chengde Medical University, Anyuan Road, Chengde 067000, People’s Republic of China
Neurodevelopmental disorders (NDDs) are extremely heterogeneous diseases that can persist throughout the whole life of patients. For some NDDs, molecular etiology diagnosis is of great significance in formulating individualized therapy.
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