Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA).

Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency.

Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach.

Case Report: Reinterpretation and Reclassification of :p.Arg159Cys Variant Identified in an Emirati Patient With Hearing Loss Caused by a Pathogenic Variant in the Gene.

Arylsulfatase B is an enzyme present in the lysosomes that involves in the breakdown of large sugar molecules known as glycosaminoglycans (GAGs). Arylsulfatase B chemically modifies two GAGs, namely, dermatan sulfate and chondroitin sulfate, by removing the sulfate group. Mutations in the gene encoding the arylsulfataseB enzyme causes lysosomal storage disorder, mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome.

Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive.

Here, we delineate the phenotype of two siblings with a bi-allelic frameshift variant in MMP15 gene with congenital cardiac defects, cholestasis, and dysmorphism. Genome sequencing analysis revealed a recently reported homozygous frameshift variant (c.1058delC, p.

Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.

Mutations in the transaldolase 1 (TALDO1) gene have been described in a limited number of cases. Several organs can be affected and clinical manifestations are variable, but often include liver dysfunction and/or hepatosplenomegaly. We report 4 patients presenting with liver disease: 2 with early-onset hepatocellular carcinoma (HCC).

Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients.

The variants of electron transfer flavoprotein (, ) and ETF dehydrogenase () are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations.

De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE.

Spectrum of neuro-genetic disorders in the United Arab Emirates national population.

Clinical and molecular characterization of neuro-genetic disorders among UAE national patients seen in the Genetic Clinic at Tawam hospital over a period of 3 years. A retrospective chart review of all Emirati patients assessed by clinical geneticists due to neuro-genetic disorders including global developmental delay, ASD, ID, ADHD, and epilepsy in combination with abnormalities of other organ systems. Each patient had proper assessment including detailed history, three-generation family history, developmental history and detailed physical examination looking for other system involvement.

Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.

Purpose: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition.

Methods: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable.

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation.

Biallelic loss-of-function HACD1 variants are a bona fide cause of congenital myopathy.

Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss-of-function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal-onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants.

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.

Unique Mutation in SP110 Resulting in Hepatic Veno-Occlusive Disease with Immunodeficiency.

Familial hepatic veno-occlusive disease with immunodeficiency (VODI, OMIM: 235550) is a rare form of combined immune deficiency (CID) that presents in the first few months of life with failure to thrive, recurrent infections, opportunistic infections along with liver impairment. Herein, we are describing a Pakistani patient with a homozygous novel variant in the gene, presenting with classical phenotypic manifestations of VODI. He presented at the age of 3 months with opportunistic infections and later developed liver failure.

Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endothelial Dysfunction and the Effect of Arginine and Citrulline Supplementation in Children and Adolescents With Mitochondrial Diseases.

Background: In addition to the reduced energy production, characteristic of mitochondrial disorders, nitric oxide (NO) deficiency can occur as well. The NO produced by vascular endothelial cells relaxes vascular smooth muscles, resulting in vasodilation that maintains the patency of small blood vessels and promotes blood flow through microvasculature. Endothelial dysfunction due to inability of vascular endothelium to generate enough NO to maintain adequate vasodilation can result in decreased perfusion in the microvasculature of various tissues, contributing to many complications seen in individuals with mitochondrial diseases.

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO.

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).

Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.

RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.

Objective: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.

Methods: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques.

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive.

Assessment of methylcitrate and methylcitrate to citrate ratio in dried blood spots as biomarkers for inborn errors of propionate metabolism.

Deficiency of propionyl-CoA carboxylase causes propionic acidemia and deficiencies of methylmalonyl-CoA mutase or its cofactor adenosylcobalamin cause methylmalonic acidemia. These inherited disorders lead to pathological accumulation of propionyl-CoA which is converted in Krebs cycle to methylcitrate (MCA) in a reaction catalyzed by citrate synthase. In healthy individuals where no propionyl-CoA accumulation occurs, this enzyme drives the condensation of acetyl-CoA with oxaloacetate to produce citric acid (CA), a normal Krebs cycle intermediate.

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA).

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function.

Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.