Abstract
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.
Parra A, Pascual P, Cazalla M, Arias P, Gallego-Zazo N, San-Martín EA, Silván C, Santos-Simarro F; Spanish OverGrowth Registry Initiative (SOGRI); Nevado J, Tenorio-Castano J, Lapunzina P. Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder. Clin Genet. 2024 Feb;105(2):140-149. doi: 10.1111/cge.14440. Epub 2023 Oct 30. PMID: 37904618.
Abstract
DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.
von Mueffling A, Garcia-Forn M, De Rubeis S. DDX3X syndrome: From clinical phenotypes to biological insights. J Neurochem. 2024 Sep;168(9):2147-2154. doi: 10.1111/jnc.16174. Epub 2024 Jul 8. PMID: 38976626; PMCID: PMC11449660.
Abstract
DDX3X syndrome is a neurodevelopmental disorder accounting for up to 3% of cases of intellectual disability (ID) and affecting primarily females. Individuals diagnosed with DDX3X syndrome can also present with behavioral challenges, motor delays and movement disorders, epilepsy, and congenital malformations. DDX3X syndrome is caused by mutations in the X-linked gene DDX3X, which encodes a DEAD-box RNA helicase with critical roles in RNA metabolism, including mRNA translation. Emerging discoveries from animal models are unveiling a fundamental role of DDX3X in neuronal differentiation and development, especially in the neocortex. Here, we review the current knowledge of genetic and neurobiological mechanisms underlying DDX3X syndrome and their relationship with clinical phenotypes.
Levy T, Siper PM, Lerman B, Halpern D, Zweifach J, Belani P, Thurm A, Kleefstra T, Berry-Kravis E, Buxbaum JD, Grice DE. DDX3X Syndrome: Summary of Findings and Recommendations for Evaluation and Care. Pediatr Neurol. 2023 Jan;138:87-94. doi: 10.1016/j.pediatrneurol.2022.10.009. Epub 2022 Oct 27. PMID: 36434914.
Abstract
DDX3X syndrome is a surprisingly common newly discovered genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities. Two hundred individuals with DDX3X syndrome have been described in the literature to date, with varied levels of detail. Individuals with DDX3X syndrome often have complex presentations including symptoms in the neurological, psychiatric/psychological, ophthalmologic, and gastrointestinal domains. Owing to this complex presentation, an overview of symptom prevalence, medical recommendations, and suggested medical surveillance is vital for the care and health of individuals with DDX3X syndrome. In this article, we summarize the present clinical knowledge of DDX3X syndrome and provide recommendations for clinical assessments and care based on a comprehensive review of the existing literature and of new, not yet published DDX3X syndrome cohorts. As more is learned about DDX3X syndrome, we anticipate that these recommendations will evolve.
See: https://childnervoussystem.blogspot.com/2022/09/ddx3x-related-neurodevelopmental.html
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