CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct.
CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct.
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DOI：
10.1007/s00439-023-02581-x
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发表时间：
2023-10
期刊：
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
内淋巴囊、导管和前庭导水管 (EVA) 增大是感音神经性听力损失患者中最常见的内耳畸形。 EVA 与 SLC26A4 的致病性变异相关。然而，在欧洲-白种人群体中，约 50% 的 EVA 患者不携带 SLC26A4 致病等位基因。我们在 34 个不带 SLC26A4 致病等位基因的 EVA 受试者家庭队列中测试了 CHD7 变异的存在，CHD7 是一种已知与 CHARGE 综合征、卡尔曼综合征和低促性腺激素性性腺功能减退症相关的基因。在两个家族中，NM_017780.4：c.3553A > G [p.(Met1185Val)] 和 c.5390G > C [p.(Gly1797Ala)] 在 EVA 患者中被检测为单等位基因 CHD7 变异。每个家庭中至少有一名受试者具有 CHARGE 综合征的其他体征或潜在体征，但不符合 CHARGE 的诊断标准。这两种错义取代的计算机模型预测了对 CHD7 蛋白质结构的有害影响。与CHD7在该组织中的作用一致，在发育中的小鼠内耳的内淋巴管和囊的所有上皮细胞中检测到Chd7转录物和蛋白质。这些结果表明，某些 CHD7 变异可导致非综合征性听力损失和 EVA。 CHD7 应纳入 DNA 序列分析中，以检测 EVA 患者的致病性变异。小鼠中的 Chd7 表达和突变表型数据表明，CHD7 有助于内淋巴囊和导管的形成或功能。在线版本包含可在 10.1007/s00439-023-02581-x 获取的补充材料。
Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European–Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue, Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that some CHD7 variants can cause nonsyndromic hearing loss and EVA. CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients. Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the endolymphatic sac and duct. The online version contains supplementary material available at 10.1007/s00439-023-02581-x.
影响因子：
2.7
作者：
Balendran V;Skidmore JM;Ritter KE;Gao J;Cimerman J;Beyer LA;Hurd EA;Raphael Y;Martin DM
通讯作者：
Martin DM