Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

Vorster, Alvera; Beighton, Peter; Ganie, Yasmeen; Henderson, B; Honey, Engela; Maré, Pieter Herman; Thompson, David M.; Fieggen, Karen; Viljoen, Denis; Ramesar, Raj

doi:10.7196/samj.2017.v107i5.9461

Cited by 12 publications

(9 citation statements)

References 28 publications

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“…South Africa is home to a diverse population with genetically unique subpopulation groups, some of which are rich in genetic founder variants, likely introduced as a direct result of the country's unique immigration and migration history and cultural norms. Examples of these disorders include variegate porphyria [ 17 ], glutaric aciduria type 1 [ 18 ], familial hypercholesterolemia [ 19 , 20 ], cystinosis [ 21 ], galactosemia [ 22 ], osteogenesis imperfecta [ 23 , 24 ], isovaleric acidaemia [ 25 ] and MPV17 neurohepatopathy [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa

Meldau

Fratter

Bhengu

et al. 2020

Molecular Genetics and Metabolism Reports

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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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Section: Discussionmentioning

confidence: 99%

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa

Meldau

Fratter

Bhengu

et al. 2020

Molecular Genetics and Metabolism Reports

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“…(Gly278Argfs * 95), was reported both for OI and BS, but not for KS in several population groups worldwide (Alanay et al, 2010;Shaheen et al, 2011;Kelley et al, 2011;Schwarze et al, 2013a;Caparros-Martin et al, 2013Vorster et al, 2017;Mrosk et al, 2018;Xu et al, 2017;Umair et al, 2016;Alabdullatif et al, 2017). Several reports describe inter-and intra-familial variability encompassing both BS and OI related phenotypes (Alanay et al, 2010;Shaheen et al, 2010Shaheen et al, , 2011Kelley et al, 2011;Schwarze et al, 2013a;Caparros-Martin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

New insights on the clinical variability of FKBP10 mutations

Essawi

Tapaneeyaphan

Symoens

et al. 2020

European Journal of Medical Genetics

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To date 45 autosomal recessive disease-causing variants are reported in the FKBP10 gene. Those variant were found to be associated with Osteogenesis Imperfecta (OI) for which the hallmark phenotype is bone fractuers or Bruck Syndrome (BS) where bone fractures are accompanied with contractures. In addition, a specific homozygous FKBP10 mutation (p.Tyr293del) has been described in Yup'ik Inuit population to cause Kuskokwim syndrome (KS) in which contractures without fractures are observed. Here we present an extended Palestinian family with 10 affected individuals harboring a novel homozygous splice site mutation, c.391+4A > T in intron 2 of the FKBP10 gene, in which the three above mentioned syndromes segregate as a result of skipping of exon 2 and absence of the FKBP65 protein. At the biochemical level, Hydroxylysyl pyridinoline (HP)/lysyl pyridinoline (LP) values were inversely correlated with OI phenotypes, a trend we could confirm in our patients. Our findings illustrate that single familial FKBP10 mutations can result in a phenotypic spectrum, ranging from fractures without contractures, to fractures and contractures and even to only contractures. This broad intrafamilial clinical variability within one single family is a new finding in the field of bone fragility.

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“…The molecular findings are not commented on further as they are the subject of a focused genetic and molecular publication. 8 …”

Section: Methodsmentioning

confidence: 99%

Craniofacial manifestations in osteogenesis imperfecta type III in South Africa

2017

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Objectives:Osteogenesis imperfecta type III (OMIM 259420) is a severe autosomal recessive disorder. Affected individuals have multiple fractures, develop limb deformities with spinal malalignment and stunted stature.Materials and methods:The frequency of Osteogenesis imperfecta type III (OI III) is relatively high in the indigenous Black African population of South Africa. A review of the literature revealed a paucity of information regarding the craniofacial manifestations of the disorder in this ethnic group. The findings in 64 affected persons are documented.Results:These abnormalities are related to the abnormal bone matrix which results in a deformed skull and dental malocclusion. The physiological process of swallowing may be an aetiological factor in the progressive development of a flattened palate. Mild changes in the shape of the head of the mandibular condyle and a lack of cortical bone on the joint surfaces were observed on cone beam computed tomography (CBCT) images. Affected persons had marked variations in the paranasal sinuses, including sinus hypoplasia and partial opacification. Cranial base anomalies were diagnosed from cephalometric radiographs and lateral skull radiographs. Platybasia and a ‘J’ shaped sella turcica were observed.Conclusion:The craniofacial abnormalities emphasize the importance of a raised level of awareness in terms of dental management and the challenges.

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Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

Cited by 12 publications

References 28 publications

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa

Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa

New insights on the clinical variability of FKBP10 mutations

Craniofacial manifestations in osteogenesis imperfecta type III in South Africa

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