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Background Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30% of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD. Methods DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized. Results Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67%) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable. Conclusions Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions. Keywords Autosomal recessive polycystic kidney disease * ARPKD * PKHD1 * Afrikaner population * Founder mutation, Introduction Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is an important childhood nephropathy [1]. The clinical phenotype is dominated by dilatation of the renal collecting ducts, biliary dysgenesis, and [...]

Author(s): Martin Franke [1, 2]; Daniel M. Ibrahim [1, 2, 3]; Guillaume Andrey [1]; Wibke Schwarzer [4]; Verena Heinrich [2, 5]; Robert Schpflin [5]; Katerina Kraft [1, 2]; Rieke Kempfer [...]

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., (© 2024. The Author(s).)

Sirenomelia, also known as the 'mermaid malformation/syndrome', is a rare, serious congenital anomaly characterized by variable degrees of fusion of the lower limbs and associated severe malformations of the lower vertebral and genitourinary systems. In this report, we describe a series of African patients with sirenomelia. We present the clinical and radiological features of four black South African patients and illustrate some of the rarer associated abnormalities, which include asymmetrical upper limb defects, not confined to the radial ray. The clinical phenotypic overlap between caudal dysgenesis, VACTERL association and sirenomelia in our patients is highlighted, lending support to the theory that these entities may be different manifestations of a single pathogenic process.