Browsing by Subject "Medical Genetics"

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    Open Access
    A clinical and molecular investigation of two families with Simpson-Golabi-Behmel syndrome
    (2014) Pretorius, Careni Elizabeth; Fieggen, Karen; Beighton, Peter
    Includes abstract (p. 30-32). Includes bibliographical references.
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    Open Access
    Craniosynostosis in a South Africa population
    (2021) Crous, Ilse; Fieggen, Karen
    Background: Craniosynostosis refers to the premature fusion of calvarial bones which lead to restricted growth potential. Compensatory growth occurs in the dimensions not restricted by fusion and causes progressive distortion in the skull shape. The majority of craniosynostosis cases occur in isolation and are so called non-syndromic craniosynostosis. In about 30 % of all cases, anomalies are noted along with the craniosynostosis, often defining a described and recognised syndrome. The aim is to delineate the phenotype observed in a South African population. Methods: In this descriptive study, hospital records for the preceding five years were retrospectively reviewed to describe the profile of patients with craniosynostosis seen at the Red Cross War Memorial Children's Hospital in Cape Town. In addition to the retrospective review, a sub cohort of patients were prospectively phenotyped. The patients were subdivided into three groups namely: non-syndromic craniosynostosis, syndromic craniosynostosis and craniosynostosis with additional features. The last group included patients who had additional malformations or clinical findings without a syndromic diagnosis. The prevalence of phenotypic findings, teratogen exposure, birth complications, congenital malformations, surgical interventions and results of genetic testing in this cohort is described. Descriptive statistical analysis was used. Results: A total of 47 children with craniosynostosis were included in this study. Twenty-five individuals of the cohort were male, and one patient has a disorder of sexual development. Eighteen patients had non-syndromic synostosis. Twelve of these had sagittal type synostosis and five had metopic type synostosis with one unspecified. Thirteen had syndromic synostosis. Eight were clinically diagnosed with Crouzon syndrome of which three were molecularly confirmed. Four patients had Apert syndrome and one had Pfeiffer syndrome, these were clinically diagnosed without molecular confirmation. Sixteen patients had craniosynostosis with some additional findings but no syndromic diagnosis. The suture involved in the majority of patients was the sagittal suture. Ten patients had an additional structural brain abnormality and 13 had signs of raised intracranial pressure. The average age at confirmation of diagnosis of craniosynostosis by CT scan was 22.5 months (SD = 31.4, range: 0.1 – 140.9). Thirty of the 47 patients had craniosynostosis surgery. The average age of surgery was 22.4 months (SD = 19; range: 5-79). The anthropometric, phenotype and developmental features indicate that this is a highly heterogenous group of disorders. Conclusion: Craniosynostosis has been widely reported worldwide, especially in individuals of European descent with only a few reports on craniosynostosis in South African or African populations. Knowledge of the phenotypic spectrum will aid in understanding and documenting this group of disorders in our local population. This study also highlights that this is a complex condition best managed by a multidisciplinary team that should include a medical geneticist. The recognition of specific craniosynostosis syndromes together with appropriate molecular testing can be cost effective even in a limited resource setting and aid in accurate prognosis and recurrence risk information for families.
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    Open Access
    Genetic investigation of South Africans with the Noonan Syndrome phenotype using targeted next generation sequencing
    (2017) Ngongang Tekendo, Cedrik; Wonkam, Ambroise; Esterhuizen, Alina
    Introduction: Noonan Syndrome (NS) is an autosomal dominant multisystem disorder, characterised by short stature, distinctive facial dysmorphism, cardiovascular abnormalities and developmental delay. Its estimated incidence is 1:1000 to 1:2500 live births. NS is caused by germline mutations in more than ten genes encoding proteins integral to the Ras/MAPK signaling pathway. Pathogenic variants in these genes account for 70-80% of NS cases. The clinical diagnosis of NS can be challenging in some cases, even when performed by experienced clinicians. The introduction of Next Generation Sequencing (NGS) technology in clinical practice in the Western world has tremendously facilitated the molecular diagnosis of RASopathies. Molecular testing for NS is not yet available in South Africa, nor has any study investigating NS from clinical and molecular perspectives been conducted in South Africans. Aim: The aim of this study was to investigate selected genes within a group of paediatric and adult patients with a clinical diagnosis of NS. Methods: This study was a cross-sectional descriptive study, including twenty-six familial and isolated NS patients recruited in Cape Town in the period January 2015-January 2017. Thorough phenotyping of each patient according to the international diagnostic criteria for NS was followed by targeted NGS, performed on leucocyte DNA samples from sixteen unrelated patients out of the twenty-six included. Sequencing involved all the exons and intron-exon boundaries of a predesigned panel of 14 genes, including A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1 and SPRED1. Results: Of the 26 patients included, 50% had a family history suggestive of NS. The median age at diagnosis was4.5 years (range: 1month-51years). Individuals of mixed-race ancestry were most represented (53.8%), followed by black Africans (30.8%). The clinical features identified were consistent with those reported in other populations. Compared to other series, our cohort revealed a lower frequency of Pulmonary Valve Stenosis (34.6%) and a less severe developmental phenotype. Variants predicted pathogenic were detected in 7(43.7%) DNA samples out of the 16 analysed. The genes involved were CBL in three cases (42.8%), PTPN11and MAP2K1in two cases (28.6%, for each gene). Surprisingly, the proportion of CBL variants was relatively high compared to those in the literature. Genotype-phenotype correlations showed that clinical features of NS were more typical in patients with pathogenic variants in MAP2K1, and less in those with variants in CBL. Conclusion: This is the first clinical and molecular study in South Africans with the NS phenotype. The phenotype of affected individuals with NS in South Africa is globally similar to that reported in the literature. Therefore, the use of international diagnostic criteria can effectively enable the clinical diagnosis of NS in most South African patients. These preliminary data suggest that the distribution of pathogenic variants in NS genes in South Africans may be different from that reported in other populations. Finally, this study demonstrates that Targeted NGS can be successfully applied to the molecular diagnosis of NS and related conditions in South Africa, and should be implemented in clinical practice.