A novel mitochondrial DNA variant in m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency.

Leigh syndrome is a severe progressive mitochondrial disorder mainly affecting children under the age of 5 years. It is caused by pathogenic variants in any one of more than 75 known genes in the nuclear or mitochondrial genomes. A 19-week-old male infant presented with lactic acidosis and encephalopathy following a 2-week history of irritability, neuroregression and poor weight gain.

Mutation profiling in South African patients with Cornelia de Lange syndrome phenotype.

Background: Cornelia de Lange Syndrome (CdLS) presents with a variable multi-systemic phenotype and pathogenic variants have been identified in five main genes. This condition has been understudied in African populations with little phenotypic and molecular information available.

Methods And Results: We present a cohort of 14 patients with clinical features suggestive of CdLS.

Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period.

A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments.

Timely and accurate diagnosis of rare genetic disorders is critical, as it enables improved patient management and prognosis. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement.

ABL1-related congenital heart defects and skeletal malformations syndrome in a patient from Sub-Saharan Africa: A case report highlighting novel cardiac features.

Congenital heart defects and skeletal malformations syndrome (CHDSKM; OMIM #617602) is a rare syndrome characterized by distinctive facial features, congenital cardiac lesions, failure to thrive, and skeletal abnormalities. Hearing impairment, renal, and ophthalmological abnormalities have also recently been reported. We report here the clinical and molecular phenotype of an adolescent male who presented with multisystem involvement suggestive of a connective tissue disorder.

Gordon syndrome: Dental implications and a case report.

Aim: This article describes the craniofacial and dental features of an individual with Gordon syndrome. The dental management implications and considerations of treating patients with Gordon Syndrome and similar conditions resulting in limited mouth opening are discussed.

Methods: A 14-year-old South African male was referred to the Dental Genetics Clinic with the main complaint of carious teeth.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

Objective: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.

A recurrent mutation causing Melnick-Needles syndrome in females confers a severe, lethal phenotype in males.

Melnick-Needles syndrome (MNS; MIM 309350) is an X-linked skeletal dysplasia caused by mutations in FLNA. Females with the condition present with characteristic facial features, short stature, skeletal anomalies, including poorly modeled and sclerotic bones, and structural abnormalities such as cardiac and urological defects. Previously males were thought to present with either a mild phenotype compatible with life or a severe lethal presentation depending on the maternal phenotype.

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein.

Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia.

Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene.

Discordant monoamniotic twins with Pena-Shokeir phenotype.

Pena-Shokeir phenotype is a rare disorder. However, its etiology is incompletely understood. It may be familial or may be due to anoxic-ischemic etiology.

A clinical and molecular investigation of two South African families with Simpson-Golabi-Behmel syndrome.

Background: Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive overgrowth syndrome manifesting primarily in boys and characterised by macrosomia, distinctive facial features and multiple congenital abnormalities. Although this rare condition is thought to be underdiagnosed, making a diagnosis is important as affected boys have a 7.5% risk of developing visceral tumours and surveillance is warranted.

Implications of direct-to-consumer whole-exome sequencing in South Africa.

This editorial examines a number of vitally important ethical, legal and scientific concerns that have to be addressed to ensure proper and ethical implementation of direct-to-consumer whole-exome sequencing in South Africa. Individuals taking part in this endeavour must be fully informed of the positive and negative sequelae.