Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Service d'Endocrinologie Pédiatrique, CHU Bordeaux, Bordeaux, France.
Clin Genet. 2018 Feb;93(2):374-377. doi: 10.1111/cge.13074. Epub 2017 Sep 29.
Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m G post transcriptional modification of tRNA. We report here 2 sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first 2 described patients: they both have a severe microcephaly but only one of the 2 sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a growth hormone deficiency and a partial hypogonadotropic hypogonadotropism. One of the 2 variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these 2 sisters allow us to confirm that biallelic variants in the WDR4 gene can lead to a specific phenotype, characterized by severe growth retardation and microcephaly.
小头畸形性原基侏儒症是一组罕见的孟德尔疾病，其特征为严重的生长迟缓及小头畸形。分子基础呈异质性，致病基因涉及不同的细胞功能。最近，有 2 例患者报道存在 WDR4 基因的纯合变异，该基因编码负责 tRNA 的 mG 后转录修饰的酶。我们在此报道 2 例存在 WDR4 复合杂合变异的姐妹。她们的表型与前 2 例描述的患者不同：她们均有严重的小头畸形，但只有 1 例姐妹在出生时头围低于-2SD，她们的智力缺陷较轻，且存在生长激素缺乏和部分促性腺激素缺乏。其中 1 个变异是移码突变，另一个是发生在第一个报道的致病性变异影响的相同核苷酸的错义变异，因此可能是一个突变热点。这 2 例姐妹的描述使我们能够确认 WDR4 基因的双等位基因变异可导致特定的表型，其特征为严重的生长迟缓及小头畸形。
