Vecchio Davide, Macchiaiolo Marina, Gonfiantini Michaela V, Panfili Filippo M, Petrizzelli Francesco, Liorni Niccolò, Cortellessa Fabiana, Sinibaldi Lorenzo, Rana Ippolita, Agolini Emanuele, Cocciadiferro Dario, Colantoni Nicole, Semeraro Michela, Rizzo Cristiano, Deodati Annalisa, Cotugno Nicola, Caggiano Serena, Verrillo Elisabetta, Nucci Carlotta G, Alkan Serpil, Saraiva Jorge M, De Sá Joaquim, Almeida Pedro M, Krishna Jayanth, Buonuomo Paola S, Martinelli Diego, Dionisi Vici Carlo, Caputo Viviana, Bartuli Andrea, Novelli Antonio, Mazza Tommaso
Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Bioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy.
Front Genet. 2024 Dec 11;15:1477940. doi: 10.3389/fgene.2024.1477940. eCollection 2024.
Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in gene (MIM#611549) resulting in a loss-of-function effect.
We enrolled a new IHPRF1 patients' cohort in the framework of an international multicentric collaboration study. Using specialized pathogenicity predictors and structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.
To date 38 different variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex.
By widening the functional spectrum of biallelic variants affecting the gene, this article broadens the IHPRF1 syndrome's genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.
伴有精神运动发育迟缓及特征性面容的婴儿型肌张力减退-1（IHPRF1，MIM#615419）是一种罕见的、出生时起病的常染色体隐性疾病，由基因（MIM#611549）中的纯合或复合杂合截短变异引起，导致功能丧失效应。
在一项国际多中心合作研究框架内，我们纳入了一个新的IHPRF1患者队列。使用专门的致病性预测因子和结构分析，我们评估了在NALCN结构和功能上检索到的有害变异的机制后果。
迄今为止，已从33个不同家庭中检索到38种不同变异，其中26种来自无关患者，22种来自相关患者。我们报告了来自四个不同家庭的五名新的IHPRF1患者，他们携带四种新鉴定的变异和一种先前检索到的变异，这些变异表现出明显显著的功能影响，从而损害了蛋白质复合物的功能。
通过拓宽影响该基因的双等位基因变异的功能谱，本文拓宽了IHPRF1综合征的基因型-表型相关性，并为其致病机制、诊断和临床管理提供了新的见解。
