Phenotypic expansion in DDX3X - a common cause of intellectual disability in females.

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.

Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.

BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects. METHODS: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis. RESULTS: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother. CONCLUSIONS: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

Basic medical genetics for the otolaryngologist.

Medical genetics is becoming an increasingly important part of the practice of medicine across every medical specialty. For otolaryngologists, understanding the genetic basis of hearing loss, tumors of the head and neck and other otolaryngologic conditions is crucial to effectively incorporating medical genetics information, tools and services into patient care. A clinician who understands the genetic basis of disease, mechanisms of genetic mutation and patterns of inheritance will be positioned to diagnose genetic conditions, interpret genetic test results, assess genetic risks for relatives of patients and refer patients and families for medical genetics and other specialty care. The family medical history is an indispensible tool that, when used properly, can aid in the recognition of genetic susceptibilities within a family and offer opportunities for early intervention. However, obtaining a family medical history is not as simple as it might seem. Knowing what questions to ask, how to properly draw a pedigree and how to recognize patterns of inheritance are critical to obtaining an informative family medical history and using the information in a clinical setting. This article provides a brief introduction to basic medical genetics that includes descriptions of the human genome, the genetic basis of human disease and patterns of inheritance, and a primer for collecting family medical history information.