Identification of two recurrent mutations of COL1A1 gene in Chinese Van der Hoeve syndrome patients

<p><b>Conclusion</b>: The two discovered mutations in <i>COL1A1</i> gene, although first reported in China, are recurrent ones that have also been found elsewhere in type I osteogenesis imperfecta patients, suggesting their role in pathogenesis of Van der Hoeve syndrome. <b>Objectives</b>: The aim of this study is to find mutational patterns of <i>COL1A1</i> gene that may account for the putative Van der Hoeve syndrome in the patients carrying symptoms of osteogenesis imperfecta, blue sclera, and conductive deafness. <b>Method</b>: Genomic DNA was extracted from the blood of each patient and exons of <i>COL1A1</i> gene were amplified using PCR and sequenced. <b>Results</b>: Sequencing in some of the two family members revealed point mutations in exon 26 (c.1792C > T) and exon 43 (c.3076C > T) of <i>COL1A1</i> gene, respectively.</p

<i>KCNJ10</i> May Not Be a Contributor to Nonsyndromic Enlargement of Vestibular Aqueduct (NSEVA) in Chinese Subjects

<div><p>Background</p><p>Nonsyndromic enlargement of vestibular aqueduct (NSEVA) is an autosomal recessive hearing loss disorder that is associated with mutations in <i>SLC26A4</i>. However, not all patients with NSEVA carry biallelic mutations in <i>SLC26A4</i>. A recent study proposed that single mutations in both <i>SLC26A4</i> and <i>KCNJ10</i> lead to digenic NSEVA. We examined whether <i>KCNJ10</i> excert a role in the pathogenesis of NSEVA in Chinese patients.</p><p>Methods</p><p><i>SLC26A4</i> was sequenced in 1056 Chinese patients with NSEVA. <i>KCNJ10</i> was screened in 131 patients who lacked mutations in either one or both alleles of <i>SLC26A4.</i> Additionally, <i>KCNJ10</i> was screened in 840 controls, including 563 patients diagnosed with NSEVA who carried biallelic <i>SLC26A4</i> mutations, 48 patients with nonsyndromic hearing loss due to inner ear malformations that did not involve enlargement of the vestibular aqueduct (EVA), 96 patients with conductive hearing loss due to various causes, and 133 normal-hearing individuals with no family history of hereditary hearing loss.</p><p>Results</p><p>925 NSEVA patients were found carrying two-allele pathogenic <i>SLC26A4</i> mutations. The most frequently detected <i>KCNJ10</i> mutation was c.812G>A (p.R271H). Compared with the normal-hearing control subjects, the occurrence rate of c.812G>A in NSEVA patients with lacking mutations in one or both alleles of <i>SLC26A4</i> had no significant difference(1.53% vs. 5.30%, χ² = 2.798, p = 0.172), which suggested that it is probably a nonpathogenic benign variant. <i>KCNJ10</i> c.1042C>T (p.R348C), the reported EVA-related mutation, was not found in patients with NSEVA who lacked mutations in either one or both alleles of <i>SLC26A4.</i> Furthermore, the normal-hearing parents of patients with NSEVA having two <i>SLC26A4</i> mutations carried the <i>KCNJ10</i> c.1042C>T or c.812G>A mutation and a <i>SLC26A4</i> pathogenic mutation.</p><p>Conclusion</p><p><i>SLC26A4</i> is the major genetic cause in Chinese NSEVA patients, accounting for 87.59%. <i>KCNJ10</i> may not be a contributor to NSEVA in Chinese population. Other genetic or environmental factors are possibly play a role in the etiology of Chinese EVA patients with zero or monoallelic <i>SLC26A4</i> mutation.</p></div

Genotype of NSEVA patients with zero or one allele <i>SLC26A4</i> mutation.

<p>wt: wild-type.</p><p>Genotype of NSEVA patients with zero or one allele <i>SLC26A4</i> mutation.</p

The KCNJ10 c.812G>A mutation identified in Chinese patients with nonsyndromic enlargement of vestibular aqueduct (NSEVA).

<p>wt, wild-type; P, father of proband (paternal); M, mother of proband (maternal).</p><p>The KCNJ10 c.812G>A mutation identified in Chinese patients with nonsyndromic enlargement of vestibular aqueduct (NSEVA).</p

Genotype of NSEVA patients with two-allele <i>SLC26A4</i> mutations.

<p>Genotype of NSEVA patients with two-allele <i>SLC26A4</i> mutations.</p

Identification of the <i>KCNJ10</i> c.1042C>T mutation in three NSEVA pedigrees with biallelic mutations in <i>SLC26A4</i>.

<p>wt, wild-type; P, father of proband (paternal); M, mother of proband (maternal); S, sibling of proband.</p><p>Identification of the <i>KCNJ10</i> c.1042C>T mutation in three NSEVA pedigrees with biallelic mutations in <i>SLC26A4</i>.</p

Mutation Spectrum of Common Deafness-Causing Genes in Patients with Non-Syndromic Deafness in the Xiamen Area, China

<div><p>In China, approximately 30,000 babies are born with hearing impairment each year. However, the molecular factors causing congenital hearing impairment in the Xiamen area of Fujian province have not been evaluated. To provide accurate genetic testing and counseling in the Xiamen area, we investigated the molecular etiology of non-syndromic deafness in a deaf population from Xiamen. Unrelated students with hearing impairment (<i>n</i> = 155) who attended Xiamen Special Education School in Fujian Province were recruited for this study. Three common deafness-related genes, <i>GJB2</i>, <i>SLC26A4</i>, and <i>mtDNA12SrRNA</i>, were analyzed using all-exon sequencing. <i>GJB2</i> mutations were detected in 27.1% (42/155) of the entire cohort. The non-syndromic hearing loss (NSHL) hotspot mutations c.109G>A (p.V37I) and c.235delC were found in this population, whereas the Caucasian hotspot mutation c.35delG was not. The allelic frequency of the c.109G>A mutation was 9.03% (28/310), slightly higher than that of c.235delC (8.39%, 26/310), which is the most common <i>GJB2</i> mutation in most areas of China. The allelic frequency of the c.109G>A mutation was significantly higher in this Xiamen’s deaf population than that in previously reported cohorts (P = 0.00). The <i>SLC26A4</i> mutations were found in 16.77% (26/155) of this cohort. The most common pathogenic allele was c.IVS7-2A>G (6.13%, 19/310), and the second most common was the c.1079C>T (p.A360V) mutation (1.94%, 6/310) which has rarely been reported as a hotspot mutation in other studies. The mutation rate of <i>mtDNA12SrRNA</i> in this group was 3.87% (6/155), all being the m.A1555G mutation. These findings show the specificity of the common deaf gene-mutation spectrum in this area. According to this study, there were specific hotspot mutations in Xiamen deaf patients. Comprehensive sequencing analysis of the three common deaf genes can help portray the mutation spectrum and develop optimal testing strategies for deaf patients in this area.</p></div

<i>GJB2</i> genotypes of deaf patients from Xiamen special education school.

<p><i>GJB2</i> genotypes of deaf patients from Xiamen special education school.</p

<i>SLC26A4</i> genotypes of deaf patients from Xiamen special education school.

<p>Note:</p><p>*: stop codon</p><p><i>SLC26A4</i> genotypes of deaf patients from Xiamen special education school.</p

Protein alignment showing conservation of residues GJB2 V670 across six species.

<p>An alignment of the SLC26A4 amino acid sequence of six species suggested the evolutionary conservation of c.2009T>C (p.V670A).</p