RNA分析揭示先天性角化不良的致病性PARN变异。

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Daria Akimova, Natalia Semenova, Tatiana Cherevatova, Mikhail Skoblov
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引用次数: 0

摘要

先天性角化不良(DC)是一种罕见的由端粒维持功能受损引起的遗传性疾病,其临床表现多样,包括骨髓衰竭、粘膜皮肤异常和多器官功能障碍。在此,我们报告一位14岁的男性患者,表现为小头畸形、发育迟缓、滑膜闭锁、小脑发育不全伴共济失调和免疫缺陷,但缺乏典型的DC特征,如指甲营养不良和皮肤色素沉着。WGS揭示了PARN基因的两个变体:一个已知的致病错义变体(C . 1045c > T, p.Arg349Trp)和一个新的内含子变体(C .178- 28t > C)。功能性RNA分析表明,内含子变异破坏分支点序列,导致显着外显子4跳变和大量转录本的无义介导衰变(NMD)。这项研究证实了内含子变异的致病性,并强调了功能验证在解释非编码变异方面的重要性,特别是在遗传异质性疾病如DC中。我们的研究结果扩展了parn相关DC的分子和表型谱,并强调了WGS再分析和RNA研究在解决诊断上具有挑战性的病例中的应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
RNA Analysis Uncovers Pathogenic PARN Variant in Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is a rare genetic disorder caused by impaired telomere maintenance, leading to diverse clinical manifestations, including bone marrow failure, mucocutaneous abnormalities, and multi-organ dysfunction. Here, we report a 14-year-old male patient presenting with microcephaly, developmental delay, synostoses, cerebellar hypoplasia with ataxia, and an immunodeficiency condition, but lacking classical DC features such as nail dystrophy and skin hyperpigmentation. WGS revealed two variants in the PARN gene: a known pathogenic missense variant (c.1045C > T, p.Arg349Trp) and a novel intronic variant (c.178-28T > C). Functional RNA analysis demonstrated that the intronic variant disrupts the branch point sequence, leading to exon 4 skipping and nonsense-mediated decay (NMD) of a significant proportion of transcripts. This study confirms the pathogenicity of the intronic variant and underscores the importance of functional validation in interpreting noncoding variants, particularly in genetically heterogeneous disorders like DC. Our findings expand the molecular and phenotypic spectrum of PARN-related DC and highlight the utility of WGS reanalysis and RNA studies in resolving diagnostically challenging cases.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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