Genotype-phenotype spectrum and correlation of PHARC Syndrome due to pathogenic ABHD12 variants.

IF 2.1 4区 医学 Q3 GENETICS & HEREDITY
Xicui Long, Wenyu Xiong, Xuegang Wang, Jia Geng, Mingjun Zhong, Yu Huang, Man Liu, Fengxiao Bu, Jing Cheng, Yu Lu, Huijun Yuan
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

致病性 ABHD12 变体导致的 PHARC 综合征的基因型-表型谱和相关性。
背景:全面了解罕见病的遗传基础及其调控机制对人类分子遗传学至关重要。然而,中国人群中致病基因突变谱的代表性仍然不足。在此,我们报告了两个中国家庭中以前未报告的 ABHD12 功能变异,并探讨了遗传多态性与 PHARC 综合征相关表型之间的相关性:从中国耳聋遗传队列中招募了具有双倍拷贝致病性ABHD12变异的参与者。这些参与者接受了全基因组测序。随后进行了全面的文献综述:结果:发现了两个汉族家庭,其中一个家庭有一个复合杂合变异体,另一个家庭有一个新的 ABHD12 同源变异体。在 65 名 PHARC 患者中,包括 62 名文献中的患者和 3 名本研究中的患者,约 90% 的患者(63 人中有 57 人)有听力损失,82% 的患者(61 人中有 50 人)有白内障,82% 的患者(56 人中有 46 人)有视网膜色素变性,79% 的患者(53 人中有 42 人)有多发性神经病,63% 的患者(57 人中有 36 人)有共济失调。在 PHARC 综合征的五种主要表型中观察到 17 种不同的模式。在 ABHD12 中总共发现了 33 个致病变体。与其他基因型相比,具有双拷贝截短变体的个体多发性神经病的发病率更高(p = 0.006),但在听力损失、共济失调、视网膜色素变性和白内障的发病率方面没有观察到显著的统计学差异:结论:由于 PHARC 综合征的遗传异质性,其诊断具有挑战性。结论:由于 PHARC 综合征的遗传异质性,其诊断具有挑战性。因此,探索新型变体并建立基因型与表型之间的相关性可大大提高对这种复杂疾病的基因诊断和遗传咨询。
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来源期刊
BMC Medical Genomics
BMC Medical Genomics 医学-遗传学
CiteScore
3.90
自引率
0.00%
发文量
243
审稿时长
3.5 months
期刊介绍: BMC Medical Genomics is an open access journal publishing original peer-reviewed research articles in all aspects of functional genomics, genome structure, genome-scale population genetics, epigenomics, proteomics, systems analysis, and pharmacogenomics in relation to human health and disease.
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