Identification of a novel mutation in a Chinese family with Nance-Horan syndrome by whole exome sequencing

Abstract

Abstract:Objective: Nance-Horan syndrome (NHS) is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the reported cases. The purpose of this study was to investigate the genetic and clinical features of NHS in a Chinese family. Methods: Whole exome sequencing analysis was performed on DNA from an affected male to scan for candidate mutations on the X-chromosome. Sanger sequencing was used to verify these candidate mutations in the whole family. Clinical and ophthalmological examinations were performed on all members of the family. Results: A combination of exome sequencing and Sanger sequencing revealed a nonsense mutation c.322G>T (E108X) in exon 1 of NHS gene, co-segregating with the disease in the family. The nonsense mutation led to the conversion of glutamic acid to a stop codon (E108X), resulting in truncation of the NHS protein. Multiple sequence alignments showed that codon 108, where the mutation (c.322G>T) occurred, was located within a phylogenetically conserved region. The clinical features in all affected males and female carriers are described in detail. Conclusions: We report a nonsense mutation c.322G>T (E108X) in a Chinese family with NHS. Our findings broaden the spectrum of NHS mutations and provide molecular insight into future NHS clinical genetic diagnosis.

A novel NHS mutation causes Nance-Horan Syndrome in a Chinese family

“…Mutations in the NHS gene have been reported from various populations throughout the world, including Turkish, Indian, Tunisian, Australian, Taiwanese, European and Chinese populations. Clinical evaluation of the available affected male subjects revealed typical NHS ocular and nonocular features that are more severe than in obligate carriers, in concordance with previous reports [8, 11, 17]. Both affected male subjects experienced profound vision loss, and one (II: 5) underwent cataract surgery.…”

“…The two major isoforms, NHS-A and NHS-1A, are transcribed from exon 1 and comprise 1630 amino acids and 1651 amino acids, respectively. NHS-B, a 1335-amino acid protein, is transcribed from exon 1b; NHS-C, a 1453-amino acid protein, is transcribed from exon 1a [8–10]. …”

Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract

“…It is also of great value in locating the causative gene of, and rare mutations in, diseases afflicting small families and sporadic cases, because of its high efficiency. Hong et al (2014) compared 3 male patients with, and 2 female carriers of, NanceHoran syndrome in four generations of a Chinese family and in 2 normal male controls, using WES in combination with Sanger sequencing, and successfully identified a new mutation c.322G>T (E108X) in exon 1 of NHS correlated with Nance-Horan syndrome in these patients.…”

“…This mutation was identified in four female patients with Y center lens opacity, and in 2 female and 3 male asymptomatic patients, implying that this is not a causative mutation of Nance-Horan syndrome. Hong et al (2014) reported a new mutation c.322G>T (E108X) in exon 1 of NHS, located in a highly-conserved region in the NHS protein. This mutation results in the conversion of a codon for glutamate to a termination codon, changes in the cellular location of NHS, degradation of NHS mRNA, and truncations in the NHS protein.…”

Loss of Nance-Horan Syndrome b (nhsb) prevents expansion growth of retinal progenitor cells by selective up-regulation of Δ113p53

“…NHS is caused by mutations in the NHS gene found at the distal end of the X chromosome. The most frequent mutations associated with NHS are nonsense mutations predicted to result in a truncated protein (Burdon et al 2003;Ramprasad et al 2005;Florijn et al 2006;Huang et al 2007;Sharma et al 2008;Coccia et al 2009;Chograni et al 2011;Tug et al 2013;Hong et al 2014;Shoshany et al 2017;Tian et al 2017), but insertions, small deletions, and a missense mutations have also been reported (Accogli et al, 2017;Brooks et al, 2004;Burdon et al, 2003;Chograni et al, 2011;Florijn et al, 2006;Li et al, 2015). Affected males have severe bilateral congenital dense nuclear cataracts that lead to profound vision loss and usually require surgery at an early age (Burdon et al 2003;Huang et al 2007;Sharma et al 2008;Coccia et al 2009).…”