CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.

Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases.

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm).

Genetic outcomes in children with developmental language disorder: a systematic review.

Introduction: Developmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial.

Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic Variant.

Aim: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances.

Diagnostic Gene Panel Testing in (Non)-Syndromic Patients with Cleft Lip, Alveolus and/or Palate in the Netherlands.

Objectives: Clefts of the lip, alveolus and/or palate (CLA/P) are the most common craniofacial congenital malformations in humans. These oral clefts can be divided into non-syndromic (isolated) and syndromic forms. Many cleft-related syndromes are clinically variable and genetically heterogeneous, making it challenging to distinguish syndromic from non-syndromic cases.

Macrocephaly and developmental delay caused by missense variants in RAB5C.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C.

Concurrent de novo ZFHX4 variant and 16q24.1 deletion in a patient with orofacial clefting; a potential role of ZFHX4 and USP10.

A girl with a unilateral cleft lip, alveolus and palate, tooth agenesis, and mild dysmorphic features, without a specific underlying syndrome diagnosis, was genotypically characterized and phenotypically described. Cleft gene panel analysis, single-nucleotide polymorphism (SNP) array, whole genome sequencing (WGS), whole exome sequencing, and quantitative PCR (Q-PCR) analysis were used as diagnostic tests. SNP array revealed a maternal deletion at 16q24.

Phenotypic expansion of EGP5-related Vici syndrome: 15 Dutch patients carrying a founder variant.

Vici syndrome (OMIM 242840) is a very rare autosomal recessive multisystem disorder first described in 1988. In 2013, bi-allelic loss-of-function mutations in EPG5 were reported to cause Vici syndrome. Five principal diagnostic features of Vici syndrome have been proposed: agenesis of the corpus callosum, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome.

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity.

Clinical Practice Guidelines on the Treatment of Patients with Cleft Lip, Alveolus, and Palate: An Executive Summary.

Significant treatment variation exists in the Netherlands between teams treating patients with cleft lip, alveolus, and/or palate, resulting in a confusing and undesirable situation for patients, parents, and practitioners. Therefore, to optimize cleft care, clinical practice guidelines (CPGs) were developed. The aim of this report is to describe CPG development, share the main recommendations, and indicate knowledge gaps regarding cleft care.

Clinical Characteristics and Genetic Etiology of Children With Developmental Language Disorder.

Developmental language delay (DLD) is one of the most common disabilities in childhood and can negatively affect a child's communication skills and academic and/or psychosocial development. To date, an increasing number of causative genes have been identified by diagnostic techniques like next generation sequencing. An early genetic diagnosis is important to properly prepare and counsel children and parents for possible future difficulties.

Gastrointestinal symptoms in patients with isolated oligodontia and a Wnt gene mutation.

Objective: Since Wnt signaling plays an important role in both tooth agenesis and altered intestine homeostasis, the aim was to compare gastrointestinal symptoms in patients with isolated oligodontia caused by a Wnt pathway gene mutation and controls.

Methods: A case-control study was designed to compare self-reported gastrointestinal symptoms among patients with isolated oligodontia, caused by a Wnt signaling gene mutation, and fully dentate controls. The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess gastrointestinal symptoms.

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain.

De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism.

Concurrent manifestation of oligodontia and thrombocytopenia caused by a contiguous gene deletion in 12p13.2: A three-generation clinical report.

Background: Wnt and Wnt-associated pathways play an important role in the genetic etiology of oligodontia, a severe form of tooth agenesis. Loss-of-function mutations in LRP6 , encoding a transmembrane cell-surface protein that functions as a coreceptor in the canonical Wnt/b-catenin signaling cascade, also contribute to genetic oligodontia.

Methods And Results: We describe a three-generation family with hereditary thrombocytopenia and oligodontia.

Deletions and loss-of-function variants in TP63 associated with orofacial clefting.

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs).