A novel Nance-Horan syndrome mutation identified by next-generation sequencing in a Chinese family.
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ABSTRACT: Aim
To identify the disease-causing mutation in a four-generation Chinese family diagnosed with Nance-Horan syndrome (NHS).Methods
A Chinese family, including four affected patients and four healthy siblings, was recruited. All family members received ophthalmic examinations with medical histories provided. Targeted next-generation sequencing approach was conducted on the two affected males to screen for their disease-causing mutations.Results
Two male family members diagnosed with NHS manifested bilateral congenital cataracts microcornea, strabismus and subtle facial and dental abnormalities, while female carriers presented posterior Y-sutural cataracts. A novel frameshift mutation (c.3916_3919del) in the NHS gene was identified. This deletion was predicted to alter the reading frame and generate a premature termination codon after a new reading frame.Conclusion
The study discovers a new frameshift mutation in a Chinese family with NHS. The findings broaden the spectrum of NHS mutations that can cause NHS in Chinese patients.
SUBMITTER: Sun HY
PROVIDER: S-EPMC9203474 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nance-Horan Syndrome (NHS) (OMIM: 302350) is a rare X-linked developmental disorder characterized by bilateral congenital cataracts, with occasional dental anomalies, characteristic dysmorphic features, brachymetacarpia and mental retardation. Carrier females exhibit similar manifestations that are less severe than in affected males.Here, we report a four-generation Chinese family with multiple affected individuals presenting Nance-Horan Syndrome. Whole-exome sequencing combined with RT-PCR and Sanger sequencing was used to search for a genetic cause underlying the disease phenotype.Whole-exome sequencing identified in all affected individuals of the family a novel donor splicing site mutation (NM_198270: c.1045?+?2T?>?A) in intron 4 of the gene NHS, which maps to chromosome Xp22.13. The identified mutation results in an RNA processing defect causing a 416-nucleotide addition to exon 4 of the mRNA transcript, likely producing a truncated NHS protein.The donor splicing site mutation NM_198270: c.1045?+?2T?>?A of the NHS gene is the causative mutation in this Nance-Horan Syndrome family. This research broadens the spectrum of NHS gene mutations, contributing to our understanding of the molecular genetics of NHS.
| S-EPMC5219716 | biostudies-literature
Project description: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.
| S-EPMC4129093 | biostudies-literature
Project description:BackgroundNance-Horan syndrome (NHS) is an X-linked inheritance disorder characterized by bilateral congenital cataracts, and facial and dental dysmorphism. This disorder is caused by mutations in the NHS gene. However, NHS may be difficult to detect in individuals with subtle facial dysmorphism and dental abnormalities in whom congenital cataracts are the primary clinical manifestations.MethodsIn this study, we present a three-generation family with NHS. Whole exome sequencing was performed to determine the potential pathogenic variant in the proband. Further validation was explored with Sanger sequencing in 9 of the available individuals of the family and additional 200 controls.ResultsA novel truncation mutation in gene NHS (c.C4449G, p.Tyr1483Ter) was found in the proband, who presented with a long-narrow face, prominent nose and large anteverted pinnae ear, screw-driver like incisors, mild mulberry like molars, one missing maxillary second molar and malocclusion. We found this mutation was detected in 2 male patients and 4 female carriers in the family. However, the mutation was never detected in the control subjects.ConclusionsIn conclusion, we identified a novel truncation mutation in the NHS gene, which might associate with NHS. Our review on the NHS studies illustrated that NHS has significantly clinical heterogeneity. And NHS mutations in the NHS-affected individuals typically result in premature truncation of the protein. And the new mutation revealed in this study would highlight the understanding of the causative mutations of NHS.
| S-EPMC6332535 | biostudies-literature
Project description:Dentofacial anomalies may guide us to the diagnosis of many congenital and hereditary syndromes. A 9-year-old boy was diagnosed with Nance-Horan syndrome. This syndrome is an extremely rare X-linked genetic disorder which is entirely expressed in males with semi-dominant transmission which results from mutations occurring in male gametes. It is characterized by facial dysmorphism such as long face, prominent nose and mandibular prognathism, ocular abnormalities such as congenital cataract, microcornea, microphthalmia and strabismus, and dental anomalies including mulberry molars and screwdriver-shaped incisors. Heterozygous females inherit this disease and also suffer from this syndrome but in a milder form. Approximately one-third of the affected males show signs of developmental delay and intellectual abnormalities. This syndrome is very rare and the incidence of the disease has not been established so far. The present article describes the clinical and radiological features and the genetic implications of this syndrome.
| S-EPMC5644009 | biostudies-literature
Project description:BackgroundThe disease intervals for Nance-Horan syndrome (NHS [MIM 302350]) and X linked congenital cataract (CXN) overlap on Xp22.ObjectiveTo identify the gene or genes responsible for these diseases.MethodsFamilies with NHS were ascertained. The refined locus for CXN was used to focus the search for candidate genes, which were screened by polymerase chain reaction and direct sequencing of potential exons and intron-exon splice sites. Genomic structures and homologies were determined using bioinformatics. Expression studies were undertaken using specific exonic primers to amplify human fetal cDNA and mouse RNA.ResultsA novel gene NHS, with no known function, was identified as causative for NHS. Protein truncating mutations were detected in all three NHS pedigrees, but no mutation was identified in a CXN family, raising the possibility that NHS and CXN may not be allelic. The NHS gene forms a new gene family with a closely related novel gene NHS-Like1 (NHSL1). NHS and NHSL1 lie in paralogous duplicated chromosomal intervals on Xp22 and 6q24, and NHSL1 is more broadly expressed than NHS in human fetal tissues.ConclusionsThis study reports the independent identification of the gene causative for Nance-Horan syndrome and extends the number of mutations identified.
| S-EPMC1735593 | biostudies-literature
Project description:Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.
| S-EPMC2701339 | biostudies-literature
Project description:Nance-Horan syndrome is a rare X-linked developmental disorder characterized by bilateral congenital cataract, dental anomalies, facial dysmorphism, and intellectual disability. Here, we identify a patient with Nance-Horan syndrome caused by a new nonsense NHS variant. In addition, the patient presented congenital diaphragmatic hernia. NHS gene expression in murine fetal diaphragm was demonstrated, suggesting a possible involvement of NHS in diaphragm development. Congenital diaphragmatic hernia could result from NHS loss of function in pleuroperitoneal fold or in somites-derived muscle progenitor cells leading to an impairment of their cells migration.
| S-EPMC5839023 | biostudies-literature
Project description:BackgroundNance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by ophthalmologic and dental anomalies as well as dysmorphic facies. The clinical phenotype in males includes congenital cataracts, vision loss, microcornea, nystagmus, microphthalmia, glaucoma, screwdriver blade-shaped incisors, supernumerary maxillary incisors, diastema, delays, intellectual disability, and dysmorphic facies. With the evolution of array-CGH technology, a total of five kindreds with NHS have been reported in the medical literature with microdeletions encompassing the NHS gene rather than sequencing variants.MethodsThe patient is a 19-year-old male born to non-consanguineous parents with a past medical history of bilateral congenital cataracts, nystagmus, poor vision, glaucoma, screwdriver blade-shaped incisors, global developmental delay, intellectual disability, bilateral sensorineural hearing loss, axial hypotonia, and bilateral foot contractures.ResultsA chromosomal microarray (CMA) was performed and revealed a 1.83-Mb interstitial microdeletion at Xp22.2p22.13 (16,604,890-18,435,836) (GRCh37/hg19) that included NHS, CTPS2, S100G, TXLNG, RBBP7, REPS2, SCML1, RAI2, and SCML2.ConclusionHere, we report the second largest microdeletion causative of NHS which also encompasses the remaining four kindreds in hopes of offering a unique perspective at the clinical variability within NHS, investigate genes of interest, and expand the phenotype.
| S-EPMC8922954 | biostudies-literature
Project description:Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.
| S-EPMC8465299 | biostudies-literature
Project description:Objective: Waardenburg syndrome type 2 (WS2) is an autosomal dominant syndrome, characterized by bright blue eyes, hearing loss, and depigmented patches of hair and skin. It exhibits high phenotypic and genetic heterogeneity. We explored the molecular etiology in a Chinese family with WS2.Methods: We recruited a three-generation family with three affected members. Medical history was obtained from all family members who underwent detailed physical examinations and audiology tests. Genomic DNA was extracted from peripheral blood of each individual, and 139 candidate genes associated with hearing loss were sequenced using Illumina HiSeq 2000 (Illumina Inc., San Diego, CA, USA) and verified by Sanger sequencing.Results: Genetic evaluation revealed a novel nonsense heterozygous variant, NM_006941.4: c.342G>A (p.Trp114Ter) in exon 2 of the SOX10 gene in the three affected patients; no unaffected family member carried the variation. We did not detect the variation in 500 Chinese individuals with normal hearing or in 122 unrelated Chinese families with hearing loss, suggesting that it was specific to our patients.Conclusions: We identified a novel heterozygous nonsense variation in a family with syndromic hearing loss and WS2. Our findings expand the pathogenic spectrum and strengthen the clinical diagnostic role of SOX10 in patients with WS2.
| S-EPMC7708717 | biostudies-literature