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KBG syndrome is an autosomal dominant disorder caused by pathogenic variants within ANKRD11 or deletions of 16q24.3 which include ANKRD11. It is characterized by distinctive facial features, developmental delay, short stature, and skeletal anomalies. We report 12 unrelated patients where a clinical diagnosis of KBG was suspected and confirmed by targeted analyses. Nine patients showed a point mutation in ANKRD11 (none of which were previously reported) and 3 carried a 16q24.3 deletion. All patients presented with typical facial features and macrodontia. Skeletal abnormalities were constant, and the majority of patients showed joint stiffness. Three patients required growth hormone treatment with a significant increase of height velocity. Brain malformations were identified in 8 patients. All patients showed behavioral abnormalities and most had developmental delay. Two patients had hematological abnormalities. We emphasize that genetic analysis of ANKRD11 can easily reach a detection rate higher than 50% thanks to clinical phenotyping, although it is known that a subset of ANKRD11-mutated patients show very mild features and will be more easily identified through the implementation of gene panels or exome sequencing. Joint stiffness was reported previously in few patients, but it seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up.

Epilepsy with eyelid myoclonias, originally depicted by Jeavons in 1977, is a reflex epilepsy characterized by jerking of the eyelids with or without absences precipitated by eye closure or by light (eyelid myoclonia, EM), eye closure-induced EEG paroxysms and photosensitivity. Childhood-onset, female predominance and a normal development are typical features, though a mild intellectual disability has been reported. Sotos syndrome is a disorder characterized by a distinctive facial appearance, learning disability and overgrowth in childhood with macrocephaly, caused by heterozygous pathogenic variants or deletions in NSD1 gene. Generalized and focal seizures have been reported in up to 25 % of patients, though EM was never documented. Here we report the novel association of Epilepsy with EM and Sotos syndrome features in a patient with two likely pathogenic missense variants in APC2 gene.

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well-established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them. This article is protected by copyright. All rights reserved.

We performed whole exome sequencing (WES) in a patient with a clinical diagnosis of possible CHARGE syndrome, where CHD7 analysis and array CGH did not identify any pathogenic variant. The boy presented prenatal and postnatal growth retardation, bilateral coloboma, a complex heart defect, hemivertebrae, monolateral renal agenesis and dysmorphic features. WES analysis identified a de novo c.532G>A mutation leading to pGlu178Lys change in PUF60, a gene predicted to be involved in some of the clinical aspects of 8q24.3 microdeletion syndrome. In this regard, rare copy number variants (CNVs) encompassing PUF60 and a single de novo missense variant in this gene were previously described. Patients showed a similar phenotype and manipulation of zebrafish attributed to PUF60 haploinsufficiency a fraction of clinical features, while coloboma and kidney anomalies were thought to be caused by haploinsufficiency of the neighboring SCRIB gene. Our results indicate that mutations in PUF60 may be fully responsible of this clinical entity, which shows a significant overlap with CHARGE syndrome.