Department of Oto-Rhino-Laryngology, West China Hospital of Sichuan University, Chengdu, 610000, China.
Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, 610000, China.
BMC Med Genomics. 2024 Aug 9;17(1):203. doi: 10.1186/s12920-024-01984-7.
A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome.
Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted.
Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts.
The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.
全面了解罕见病的遗传基础及其调控机制对于人类分子遗传学至关重要。然而，中国人群中致病基因的遗传突变谱仍然代表性不足。在这里，我们报道了两个中国家庭中以前未报道的 ABHD12 功能变体，并探讨了遗传多态性与 PHARC 综合征相关表型之间的相关性。
从中国聋病遗传学队列中招募了携带双等位致病性 ABHD12 变体的参与者。这些参与者接受了全基因组测序。随后，进行了全面的文献回顾。
确定了两个汉族家庭，一个家庭的 ABHD12 中存在复合杂合变体，另一个家庭存在新的纯合变体。在 65 名 PHARC 患者中，包括 62 名来自文献和 3 名来自本研究的患者，大约 90%（57/63）有听力损失，82%（50/61）有白内障，82%（46/56）有视网膜色素变性，42%（42/56）有周围神经病，63%（36/57）有共济失调。PHARC 综合征的五个主要表型观察到 17 种不同的模式。在 ABHD12 中总共鉴定出 33 个致病性变体。与其他基因型相比，携带双等位截断变体的个体周围神经病的发生率更高（p=0.006），但听力损失、共济失调、视网膜色素变性和白内障的发生率无统计学差异。
由于遗传异质性，PHARC 综合征的诊断具有挑战性。因此，探索新的变体并建立基因型-表型相关性可以显著提高对这种复杂疾病的基因诊断和遗传咨询。
