Kennis Milou G P, Rots Dmitrijs, Bouman Arjan, Ockeloen Charlotte W, Boelen Caroline, Marcelis Carlo L M, de Vries Bert B A, Elting Mariet W, Waisfisz Quinten, Suri Mohnish, Font-Montgomery Esperanza, Peck Dawn S, Donnelly Deirdre E, Rogers R Curtis, Richardson Ruth, Caumes Roseline, Chaumette Boris, Louveau Cécile, Sallevelt Suzanne C E H, Maas Saskia M, Smits Jeroen J, van Haelst Mieke M, Levy Rebecca J, Stewart Helen, Loeys Bart L, Pfundt Rolph, Kleefstra Tjitske, Snijders Blok Lot
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Eur J Hum Genet. 2025 Mar 31. doi: 10.1038/s41431-025-01832-x.
DDX3X-related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X variants in clinical practice. In this study, we present a new cohort of 19 affected males (from 17 unrelated families) with (possibly) disease-causing DDX3X variants, for whom we collected clinical and molecular data. Additionally, we reviewed the existing literature on 13 males with DDX3X variants. The phenotype in males is diverse, including intellectual disability, speech/language delays, behavioural challenges and structural brain abnormalities. The vast majority of males have missense variants, including two recurrent variants (p.(Arg351Gln) and p.(Arg488Cys)). No truncating variants have been reported, consistent with the presumed embryonic lethality of complete loss-of-function of DDX3X in males. In our novel cohort, 6/17 variants are de novo in the affected male and 3/17 variants are de novo in the mother. This study provides significant insights in the genetic and phenotypic spectrum of males with DDX3X variants, by presenting the data of a combined cohort (n = 32) of novel and published individuals. Our data show that variants in DDX3X can cause an X-linked neurodevelopmental disorder in males, with unaffected or mildly affected carrier females. These findings will aid the interpretation of hemizygous missense variants in DDX3X and can guide clinical management and counselling, in particular with regard to recurrence risks in the respective families.
与DDX3X相关的神经发育障碍是女性智力残疾最常见的单基因病因之一，目前全球确诊的女性患者超过1000例。相比之下，关于携带DDX3X变异的男性患者的报道却很稀少。对男性中这种X连锁疾病的了解有限，阻碍了临床实践中对半合子DDX3X变异的解读。在本研究中，我们报告了一个新队列，其中有19名受影响的男性（来自17个无亲缘关系的家庭）携带（可能）致病的DDX3X变异，我们收集了他们的临床和分子数据。此外，我们还回顾了关于13名携带DDX3X变异男性的现有文献。男性的表型多种多样，包括智力残疾、言语/语言发育迟缓、行为问题和脑结构异常。绝大多数男性具有错义变异，包括两个反复出现的变异（p.(Arg351Gln)和p.(Arg488Cys)）。尚未报道有截短变异，这与男性中DDX3X完全功能丧失的推测胚胎致死性一致。在我们的新队列中，17个变异中有6个是受影响男性的新发变异，17个变异中有3个是母亲的新发变异。本研究通过展示一个由新病例和已发表病例组成的联合队列（n = 32）的数据，对携带DDX3X变异男性的遗传和表型谱提供了重要见解。我们的数据表明，DDX3X变异可导致男性X连锁神经发育障碍，而携带变异的女性未受影响或仅有轻微影响。这些发现将有助于解读DDX3X中的半合子错义变异，并可指导临床管理和咨询，特别是关于各个家庭的复发风险。
