Abstract Intellectual disability (ID) has an estimated prevalence of 1.5%–2%. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that sporadic ID cases result from de novo mutations in genes associated with ID. Here, we report on a 10‐year‐old girl, who has been regularly presented in our neuropediatric and genetic outpatient clinic. A median cleft palate and a heart defect were surgically corrected in infancy. Apart from ID, she has behavioral anomalies, muscular hypotonia, scoliosis, and hypermobile joints. The facial phenotype is characterized by arched eyebrows, mildly upslanting long palpebral fissures, prominent nasal tip, and large, protruding ears. Trio WES revealed a de novo missense variant in MEIS2 (c.998G>A; p.Arg333Lys). Haploinsufficiency of MEIS2 had been discussed as the most likely mechanism of the microdeletion 5q14‐associated complex phenotype with ID, cleft palate, and heart defect. Recently, four studies including in total 17 individuals with intragenic MEIS2 variants were reported. Here we present the evolution of the clinical phenotype and compare with the data of known individuals.
Abstract Short stature is one of the most common reasons for a referral to the pediatric endocrinology clinic. Thousands of patients with short stature are assessed annually at the Department of Endocrine and Metabolic Diseases (DEMD) at Bab el Oued University Hospital in Algiers, Algeria. However, diagnostic rates in patients with syndromic short stature are not optimal due to the unavailability of next generation sequencing (NGS) technology. Here, we enrolled 10 Algerian patients with syndromic short stature in a pilot study to test the impact of genetic and genomic approaches in the DEMD. Using a combination of two different NGS modalities, namely exome sequencing and the Mendeliome (TruSight™ One sequencing panel) along with single gene testing, we were able to establish a confirmed molecular diagnosis in 7/10 patients (70%) and to identify strong likely disease‐causing variants in a further two patients. Novel variants in NPR2 and VPS13B were identified. Using copy number variation analysis on the exome data, we also identified a de novo deletion of the short arm of chromosome X. These definitive diagnoses have made a substantial impact on patient treatment, management and genetic counseling. Genomic testing has the ability to transform clinical practice, and is an essential diagnostic tool in any tertiary pediatric clinic, particularly in resource limited settings.
To unravel the system of epigenetic control of transcriptional regulation is a fascinating and important scientific pursuit. Surprisingly, recent successes in gene identification using high-throughput sequencing strategies showed that, despite their ubiquitous role in transcriptional control, dysfunction of chromatin-modifying enzymes can cause very specific human developmental phenotypes. An intriguing example is the identification of de novo dominant mutations in MLL2 as a cause of Kabuki syndrome, a well-known congenital syndrome that is associated with a very recognizable facial gestalt. However, the existing confusion in the nomenclature of the human and mouse MLL gene family impedes correct interpretation of scientific findings for these genes and their encoded proteins. This Review aims to point out this nomenclature pitfall, to explain its historical background, and to promote an unequivocal nomenclature system for chromatin-modifying enzymes as proposed by Allis et al. (2007).
Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2-related CREBBP activator protein (SRCAP) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition.
