Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders.

There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis.

Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.

Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes.

Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.

Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.

Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.

Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families.

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%).

Expansion of NEUROD2 phenotypes to include developmental delay without seizures.

De novo heterozygous variants in the brain-specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early-onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro).

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associated AMC as a type of viable fetal akinesia deformation sequence.

Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN-associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders.

Identification of novel mutations and phenotype in the steroid resistant nephrotic syndrome gene NUP93: a case report.

Background: Monogenic mutations may be a significant cause of steroid-resistant nephrotic syndrome. NUP93 is a gene previously reported to cause isolated steroid-resistant nephrotic syndrome.

Case Presentation: Here we describe a case of recessive, syndromic, steroid-resistant nephrotic syndrome caused by NUP93 mutation.

Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the gene: further delineation of the phenotypic spectrum.

Variants in the mitochondrial alanyl-tRNA synthetase 2 gene (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous variants in both siblings (c.

A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death.

RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.

A Novel Pathogenic Variant in a Sudanese Child with Type 1 Crigler-Najjar Syndrome.

Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body's ability to process a variety of endogenous and exogenous compounds. Significant gains in understanding UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who showed clinical features of type 1 Crigler-Najjar syndrome (CN-1), namely severe unconjugated hyperbilirubinemia leading to liver transplantation.

Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases.

Mutations in Kelch-like family member 7 (KLHL7) have recently been described as a cause of a constellation of clinical findings with descriptions of both a Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like, as well as a Bohring-Opitz syndrome (BOS)-like presentation. Here we report two siblings of Guatelmalan descent with a novel homozygous nonsense mutation (p.Arg326*) in KLHL7.