Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings

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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-year-old 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.

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Author information

Correspondence to Xiu-An Yang or De Wu.

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This study was approved by the Medical Ethics Committee in The First Hospital of Anhui Medical University. Written informed consent was obtained from the parents for the molecular genetic analysis of the related genes and the publication of this case report.

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The authors declare that they have no conflict of interest.

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Electronic Supplementary Material

Supplementary Fig. 1

No abnormalities were found in cranial magnetic resonance imaging (MRI) for the siblings (brother: A,B; sister: C,D). The bilateral cerebral hemispheres were symmetrical, with normal contrast of gray matter and white matter. No focal signal abnormalities were observed. The size and shape of each ventricle and cistern were normal. The midline structure was normal and no abnormal signal was found in the brain parenchyma. (PNG 324 kb)

Supplemental Table 1

Potential compound heterozygosity genes identified by manual analysis. (XLSX 13 kb)

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Zhang, X., Wang, Y., Yang, F. et al. Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings. J Mol Neurosci 70, 1–8 (2020).

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  • Neurodevelopmental disorder
  • Whole-exome sequencing
  • INTS1
  • INTS8
  • CTDP1