Nance–Horan syndrome pedigree due to a novel microdeletion and skewed X chromosome inactivation

• Published in: Molecular genetics & genomic medicine Vol. 11; no. 2; pp. e2100 - n/a
• Main Authors: Huang, Yazhou, Ma, Linya, Zhang, Zhaoxia, Nie, Shujuan, Zhou, Yuan, Zhang, Jibo, Wang, Chao, Fang, Xingxin, Quan, Yingting, He, Ting, Liu, Anhui, Peng, Dan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2023; John Wiley and Sons Inc; Wiley
• Subjects: Abnormalities; Androgens; Asymptomatic; Calcium-Binding Proteins - genetics; Cataract - genetics; Cataracts; Chromosomes; Congenital diseases; Copy number; copy number variation sequencing; Deactivation; dense congenital cataracts; Disease; DNA Copy Number Variations; DNA methylation; Female; Females; Frameshift mutation; Gene expression; genetic counseling; Genetic screening; Genomes; Genomics; Haploinsufficiency; Hereditary diseases; Humans; Inactivation; Intellectual disabilities; Males; Membrane Proteins - genetics; Mutation; Nance–Horan syndrome; Nuclear Proteins - genetics; Original; Patients; Pedigree; Proteins; Sequences; X Chromosome Inactivation; X chromosomes; genetic counseling; Nance-Horan syndrome; copy number variation sequencing; dense congenital cataracts; X chromosome inactivation
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2100

Background Nance–Horan syndrome (NHS) is a rare and often overlooked X‐linked dominant disorder characterized by dense congenital cataracts, dental abnormalities, and mental retardation. The majority of NHS variations include frameshift mutations, nonsense mutations, microdeletions, and insertions. Methods Copy number variation sequencing was performed to determine the microdeletion. The expression of NHS was detected by RT‐PCR. Four family members were tested for X chromosome inactivation. Results In this study, all members were examined for systemic examinations and genetic testing of four members and two affected subjects are observed. We identified a heterozygous microdeletion of −0.52 Mb at Xp22.13 in a female proband presenting NHS phenotypically. The microdeletion contains the REPS2 and NHS genes and was inherited from a phenotypically normal mother. Of interest, the expression NHS of proband was reduced and the skewed X chromosome inactivation rate reached more than 85% compared with her mother and the control. It was concluded that the haploinsufficiency of the NHS gene may account for the majority of clinical symptoms in the affected subjects. The variability among female carriers presumably results from nonrandom X chromosome inactivation. Conclusion Our findings broaden the spectrum of NHS mutations and provide molecular insight into NHS clinical prenatal genetic diagnosis. Firstly, we identified a heterozygous microdeletion of 0.52 Mb at Xp22.13 detected by genome‐wide copy number variation sequencing in a proband presenting congenital cataract, facial dysmorphisms, and mental retardation. Then, the pathogenesis was explored from gene expression level and X chromosome inactivation patterns. Lastly, it was concluded that the haploinsufficiency of the NHS gene may account for the majority of clinical symptoms in the affected subjects.