Heide Solveig, Argilli Emanuela, Valence Stéphanie, Boutaud Lucile, Roux Nathalie, Mignot Cyril, Nava Caroline, Keren Boris, Giraudat Kim, Faudet Anne, Gerasimenko Anna, Garel Catherine, Blondiaux Eleonore, Rastetter Agnès, Grevent David, Le Carolyn, Mackenzie Lisa, Richards Linda, Attié-Bitach Tania, Depienne Christel, Sherr Elliott, Héron Delphine
Department of Genetics and Referral Center for Intellectual disabilities of rare causes, AP-HP.Sorbonne Université, Assistance Publique-Hopitaux de Paris, Pitié-Salpêtrière Hospital, Paris, 75013, France, Paris, France
Department of Neurology, University of California San Francisco Division of Hospital Medicine, San Francisco, California, USA.
J Med Genet. 2024 Feb 21;61(3):244-249. doi: 10.1136/jmg-2023-109293.
The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered.
Through a collaborative work, we describe here , a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a heterozygous loss-of-function (LoF) variant, identified by exome sequencing.
In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in . All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to .
This study shows LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.
胼胝体发育异常（ACC）是最常见的脑畸形之一，其神经发育预后差异极大，从正常发育到严重智力残疾（ID）不等。已知许多基因会导致伴有ID的综合征性ACC，而不伴有ID的ACC的遗传学仍知之甚少。
通过合作研究，我们在此描述了一个先前与一种称为3型后多形性角膜营养不良的眼科疾病有关的基因，作为ACC的一个新的显性基因。我们报告了一系列9例患有ACC的个体（包括3例因ACC而终止妊娠的胎儿），通过外显子组测序鉴定出携带杂合功能丧失（LoF）变异。
在5例中，该变异从胼胝体正常的父母一方遗传而来，这说明了ACC在具有LoF变异个体中的不完全外显率。所有患者报告学业正常，且均无ID。对6例患者的神经心理学评估显示功能正常或认知异质性。此外，2例患者有双角子宫，3例有心血管异常，4例出生时头围增大，这表明与该基因相关的畸形谱更广。
本研究表明LoF变异导致显性遗传的不伴有ID的ACC，并扩展了与该基因相关的眼外表型。
