Clinical and Molecular Characterization of Xia-Gibbs Syndrome: Expanding the Phenotypic Spectrum in a Brazilian Cohort.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Maísa Ganz Sanchez Sennes, Laura Machado Lara Carvalho, Matheus Augusto Araújo Castro, Giovana Manilli Toccoli, Sofia de Oliveira Farias, Davi Mendes Campo Fialho, Eny Maria Goloni Bertollo, Erika Cristina Pavarino, Larissa Sampaio de Athayde, Cecilia Barbosa Buck, Maria Betânia Pereira Toralles, Maria Isabel Melaragno, Mariluce Riegel-Giugliani, Gustavo Marquezani Spolador, Paulo Alberto Otto, Caroline Brandão Piai, Fernando Kok, Ceres Schmitz Cechella, Carla Rosenberg, Juan Clinton Llerena, Débora Romeo Bertola, Salmo Raskin, Chong Ae Kim, Ana Cristina Victorino Krepischi
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引用次数: 0

Abstract

Xia-Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians. Genomic variants and their segregation were validated via Sanger sequencing. Statistical analyses were conducted to evaluate genotype-phenotype associations. Twelve novel AHDC1 causative variants were documented. ID, hypotonia, motor developmental delay, and varied nonspecific facial dysmorphisms were observed in all patients, while speech impairment and autism spectrum disorder were present in nearly all. Three frequent phenotypes, not previously reported, were identified: hyperphagia/food obsession, genital/gonadal alterations in males, and shortening of the Achilles tendon. Additionally, our findings provide statistically significant support for previously reported genotype-phenotype associations between pathogenic variants in the first half of the AHDC1 coding region and the occurrence of epilepsy and scoliosis. We also propose a novel association between N-terminal variants and developmental regression. In summary, our results broaden the clinical phenotype of XGS, with musculoskeletal and genital/gonadal abnormalities highlighting the multisystem involvement in this condition, beyond neurodevelopmental deficits. Comprehensive phenotypic assessments in all identified XGS cases are recommended to accurately recognize and associate novel clinical signs with XGS.

夏-吉布斯综合征的临床和分子特征:在巴西队列中扩大表型谱。
夏-吉布斯综合征(Xia-Gibbs syndrome, XGS)是一种罕见的由AHDC1致病变异引起的智力残疾(ID)综合征。我们分析了16例巴西XGS患者的临床和分子特征。通过与家庭成员的半结构化访谈、对先前健康和遗传评估的再分析以及医生的临床报告收集患者数据。基因组变异及其分离通过Sanger测序进行验证。对基因型与表型的相关性进行了统计分析。记录了12种新的AHDC1致病变异。在所有患者中都观察到ID,张力低下,运动发育迟缓和各种非特异性面部畸形,而几乎所有患者都存在语言障碍和自闭症谱系障碍。以前未报道的三种常见表型被确定:嗜食/食物强迫症,男性生殖器/性腺改变,跟腱缩短。此外,我们的研究结果为先前报道的AHDC1编码区前半部分的致病变异与癫痫和脊柱侧凸的发生之间的基因型-表型关联提供了统计学上显著的支持。我们还提出了n端变异与发育回归之间的新联系。总之,我们的研究结果拓宽了XGS的临床表型,肌肉骨骼和生殖器/性腺异常突出了这种疾病的多系统参与,而不仅仅是神经发育缺陷。建议对所有已确诊的XGS病例进行综合表型评估,以准确识别并将新的临床症状与XGS联系起来。
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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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