Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients.

Hyperphosphatasia with mental retardation syndrome (HPMRS) is a rare autosomal recessive disorder caused by pathogenic variants in genes involved in glycosylphosphatidylinositol metabolism that result in a similar phenotype. We describe the first three patients with HPMRS from sub-Saharan Africa. Detection was assisted by Face2Gene phenotype matching and confirmed by the presence of elevated serum alkaline phosphatase. All three patients had severe intellectual disability, absent speech, hypotonia and palatal abnormality (cleft palate in two, very high-arched palate in one), no or minimal brachytelephalangy, and high serum alkaline phosphatase levels. Additional findings included seizures in two, and brain imaging abnormalities in two. In all three patients HPMRS was a top-20 gestalt match using Face2Gene. The overall phenotype is consistent with descriptions in the literature of HPMRS type 4, although not specific to it. Whole exome sequencing in the index patient and his mother detected a candidate variant in a homozygous state in the index patient (PGAP3:c.557G>C, p.Arg186Thr) and heterozygous in the mother. Further variant interpretation indicated pathogenicity. Sanger sequencing of another two patients identified the same homozygous, pathogenic variant, confirming a diagnosis of HPMRS type 4. The shared homozygous variant in apparently unrelated families, and in the absence of consanguinity, suggests the possibility of genetic drift due to a population bottleneck effect, and further research is recommended.

A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials.

Affecting both mother and the existing pregnancy, tuberculosis (TB) increases the likelihood of poor birth outcomes. Despite substantial clinical need for TB prevention and treatment, pregnant women remain neglected by research initiatives. As members of 3 community advisory boards that provide input into TB drug trials, we offer a community perspective on the inclusion of pregnant women in TB drug research and discuss (1) our perspective on the risk/benefit tradeoff of including pregnant women in research to address different forms of TB; (2) recent examples of progress in this area; (3) lessons learned from the human immunodeficiency virus research field, where pregnant women have enjoyed better-although imperfect-representation in research; and (4) recommendations for different stakeholders, including researchers, regulatory authorities, ethics committees, and policymakers.

STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.

STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks.

Utility of genetic testing in children with developmental and epileptic encephalopathy (DEE) at a tertiary hospital in South Africa: A prospective study.

OBJECTIVES: The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by early-onset seizures that are often intractable, electroencephalographic abnormalities, and developmental delay or regression. There is a paucity of data from sub-Saharan Africa on the genetic basis of DEE. The aim of this study was to investigate the genetic background of DEE using targeted next generation sequencing (NGS) analysis in a tertiary pediatric neurology outpatient department at Tygerberg Hospital, South Africa. In addition, we assessed the value of the genetic results to the parents and managing physicians. METHODS: A prospective cohort study of 41 consecutive children with DEE (onset before 3 years of age) that were recruited over a 2-year period (2019-2021). Pre- and post-test genetic counselling were offered to all study participants. The results were categorized as either: positive (pathogenic/likely pathogenic variant identified), inconclusive (variant(s) of unknown significance identified), or negative (no variants identified). Result interpretation and careful matching of the variant to the clinical phenotype was performed. Subsequently, questionnaires were administered to both the physicians and the parents. RESULTS: A genetic underlying cause for DEE was identified in 18 of 41 children (diagnostic yield 43.9%). Variants in SCN1A (n=7), KANSL1 (n=2), KCNQ2 (n=2) and CDKL5 (n=2) were identified in more than one patient. Rarer genes included IQSEC2, SMC1A and STXBP1. All of the identified pathogenic variants fully explained and matched the respective phenotypic description of the patient at the time of clinical diagnosis. In 26% of patients the genetic result facilitated precision medicine management changes to anti-seizure medication. Both parents and physicians expressed benefit of genetic testing in patients with DEE. CONCLUSION: Targeted NGS analysis proved an efficient diagnostic tool in detection of a genetic cause of DEE in a large proportion of South African children. The 43.9% diagnostic yield is similar to previously reported international pediatric cohorts. Additionally, the genetic findings proved useful for targeted therapeutic decision-making and accurate genetic counseling.

CHARGE syndrome: genetic aspects and dental challenges, a review and case presentation.

BACKGROUND: CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12. CASE PRESENTATION: A South African female of mixed ancestry heritage, aged 4 years, was referred for dental assessment to the Faculty of Dentistry, University of the Western Cape, in 2018. She had a diagnosis of CHARGE syndrome confirmed by a Medical Geneticist from the Division of Molecular Biology and Human Genetics at the University of Stellenbosch. The patient had a long prior history of health and developmental problems, with the correct diagnosis becoming apparent over time. She presented with many oral and craniofacial features warranting consideration by the dentist including micrognathia, hypoplastic nasal bones, cranial nerve dysfunction, bruxism, craniofacial anomalies and compromised sensory perception. The treatment was mainly preventive and, although she fed through a percutaneous endoscopic gastrostomy tube (PEG), maintenance of her oral hygiene was necessitated. CONCLUSION: CS is a multisystem condition and the optimal care for an individual is with a specialist multidisciplinary team. The numerous systemic problems affecting these individuals take precedence in their care, and often there is neglect of their dental concerns. Given the abnormalities frequently present in the oral and craniofacial region, the authors recommend that a team of dental and other medical specialists be involved in the management of individuals with CS.