背景:全面了解罕见疾病的遗传基础及其调节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不足。这里,我们报道了两个中国家庭中以前未报道的功能性ABHD12变异,并探讨了与PHARC综合征相关的遗传多态性和表型之间的相关性.
方法:从中国耳聋遗传学队列招募具有双等位基因致病性ABHD12变异体的参与者。这些参与者进行了全基因组测序。随后,进行了全面的文献综述。
结果:确定了两个汉族家庭,一个具有复合杂合变体,另一个在ABHD12中具有新的纯合变体。在65名PHARC患者中,其中62份来自文献,3份来自本研究,大约90%(63人中有57人)表现出听力损失,82%(61人中有50人)患有白内障,82%(56人中有46人)出现色素性视网膜炎,79%(53人中有42人)经历了多发性神经病,63%(57人中有36人)表现出共济失调。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中鉴定出总共33种致病变体。与其他基因型相比,具有双等位基因截短变异的个体表现出更高的多发性神经病的发病率(p=0.006),但是在听力损失的发生率方面没有观察到统计学上的显着差异,共济失调,视网膜色素变性和白内障。
结论:由于其遗传异质性,PHARC综合征的诊断具有挑战性。因此,探索新的变异并建立基因型-表型相关性可以显著增强这种复杂疾病的基因诊断和遗传咨询.
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.