True hermaphroditism is defined by the presence of both testicular and ovarian tissue in an individual. True hermaphrodites usually present at birth with ambiguous genitalia, and subsequent invasive investigations are needed to confirm the diagnosis. Several large cohorts of black South Africans with true hermaphroditism have been described, and by far the majority of those investigated had a 46,XX karyotype, with absence of the SRY sequence. This paper represents the first report of the molecular investigation of mosiacism/chimerism as the cause of hermaphroditism in black southern African patients. It is the second report worldwide of a 46,XX/47,XY,+21 chimera, with the first described in a Japanese infant in 1994. Case 1 in the present study is a child who is a 46,XX/47,XY,+21 tetragametic chimera. Molecular studies revealed two paternal and two maternal alleles at four of ten STR loci investigated and three alleles at four of these loci. The young boy exhibited no features of Down syndrome, other than a unilateral single palmar crease. Cases 2 and 3 both have a 46,XX/46,XY karyotype. Chimerism is supported by molecular analysis in Case 2, and molecular studies were not done for Case 3.
Pyruvate dehydrogenase complex (PDHC) deficiencies are a group of mainly infantile onset disorders stemming from defects in pyruvate catabolism. They are characterised by severe lactic acidosis and progressive neurodegeneration.
Although the
PDHA1
gene is implicated in most cases of PDHC deficiency worldwide, no pathogenic variants have been reported in South African patients to date, despite availability of
PDHA1
sequencing in the state diagnostic setting.
Methods
DNA from five patients with low to absent PDHC activity in fibroblasts were subjected to PDHC deficiency gene panel analysis. Included in the panel were:
PDHA1, PDHB, DLAT, DLD, PDHX, BOLA3, GLRX5, IBA57, LIAS, LIPT1, LIPT2, NFU1, PDP1, PDP2, SLC19A2, SLC19A3, SLC25A19, SLC25A26, TPK1
and
FBXL4
.
Results
No pathogenic variants were identified in 4 out of 5 cases investigated. A homozygous frame-shift mutation was detected in the
BOLA3
gene in one patient, supporting a diagnosis of multiple mitochondrial dysfunction syndrome type 2.
Discussion
A single, novel, homozygous
BOLA3
frame-shift mutation was detected in a black South African child with severe neurodegenerative disease and very low to absent PDHC enzyme activity. This finding of a homozygous mutation in a patient from a non-consanguineous background may indicate a need for further investigation in clinically similar cases as well as heterozygous carrier rates in unaffected individuals from the same ethnic background.
The paucity of identifiable mutations in 4 out of 5 South African patients with confirmed PDHC deficiency highlights the dangers in relying on Western population based genetic panels for diagnosing rare metabolic disease in genetically understudied populations.
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