Association between MTHFR C677T variant and risk for congenital heart defects in Egyptian children: a case–control study including meta-analysis based on 147 cases and 143 controls

المجلة: Egyptian Journal of Medical Human Genetics

سنة النشر: 2023

تاريخ النشر: 2023-04-23

In this study, the association between the MTHFR C677T variant and the risk for CHDs was evaluated in 91 children with CHD and 95 healthy controls, as new cases, by using restriction fragment length polymorphism (RFLP) technique. Besides that, 2 case–control studies in the Egyptian population published before 2021 were included in this meta-analysis. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI) based on 294 alleles in CHD cases and 286 alleles in controls. Our results support the MTHFR -677T allele as a susceptibility factor for CHDs in the Egyptian pediatric patients.

Cohen syndrome and early-onset epileptic encephalopathy in male triplets: two disease-causing mutations in VPS13B and NAPB.

المجلة: Neurogenetics

سنة النشر: 2023

تاريخ النشر: 2023-02-13

Cohen syndrome (CS) is a rare multisystem autosomal recessive disorder associated with mutations in VPS13B (vacuolar protein sorting homolog 13B). The NAPB-related neurodevelopmental disorder is characterized mainly by early-onset epileptic encephalopathy (EOEE) and is associated with mutations in NAPB that encodes for SNAP-beta (soluble NSF attachment protein beta). Here we describe male triplets, clinically presenting with the phenotype of subtle but distinctive facial features, intellectual disability, increased body weight, neonatal EOEE, and prominently variable abnormal behaviors of autism and sexual arousal. The EEG showed multifocal epilepsy, while the brain MRI showed no abnormalities. Diagnostic exome sequencing (ES), the applied next-generation sequencing approach, revealed the interesting finding of two novel homozygous variants in two genes: VPS13B missense variant (c.8516G > A) and NAPB splice-site loss (c.354 + 2 T > G). Sanger sequencing verified the segregation of the two recessive gene variants with the phenotype in family members. The prediction algorithms support the pathogenicity of these variants. Homozygosity mapping of ES data of this consanguineous family revealed multiple chromosomal regions of homozygosity stretches with the residing of VPS13B (chr8: 100830758G > A) and NAPB (Chr20: 23,375,774 A > C) variants within the largest homozygous blocks further supporting the disease-genes causal role. Interestingly, the functions of the two proteins; VPS13B, a transmembrane protein involved in intracellular protein transport, and SNAP-beta involved in neurotransmitters release at the neuronal synaptic complexes, have been associated with Golgi-mediated vesicular trafficking. Our ES findings provide new insights into the pathologic mechanism underlying the expansion of the neurodevelopmental spectrum in CS and further highlight the importance of Golgi and Golgi-membrane-related proteins in the development of neurodevelopmental syndromes associated with early-onset non-channelopathy epilepsy. To our knowledge, this is the first report documenting multifocal EOEE in CS patients with the association of a pathogenic NAPB variant.

Clinical and molecular findings in eight Egyptian patients with suspected mitochondrial disorders and optic atrophy

المجلة: Egyptian Journal of Medical Human Genetics

سنة النشر: 2013

تاريخ النشر: 2013-01-24

Mitochondrial respiratory chain disorders (RCD) are a group of genetically and clinically heterogeneous diseases, caused due to defects of the respiratory chain. This study aimed to investigate the presence of common mtDNA point mutations in tRNALeu (UUR), tRNALys, MT-ATPase 6, MT-ND4, MT-ND1, MT-ND6 genes in eight Egyptian patients suspected to have mtDNA disease and optic atrophy. PCR-RFLP analysis was done for the detection of 3243A > G, 3271T > C, 8344A > G, and 8993T > G/C mtDNA point mutations. DNA direct sequencing was pursued for the detection of 11778G > A, 3460G > A and 14484T > C mtDNA point mutations. No point mutation of 3243A > G, 3271T > C, 8344A > G, and 8993T > G/C was detected in our group of patients. Four mtDNA polymorphisms in MT-ND1 and MT-ND4 genes (11467A > G, 11719G > A, 3348A > G and 3357G > A) were detected in three patients. Mitochondrial disorders are caused by a variety of genetic and racial factors, which differ among populations. The negative results of this study indicate that the chosen mutations might not be specific in Egyptians. Another explanation might be due to the low heteroplasmic levels of the mtDNA mutation. A registry for the different mtDNA mutations in Egyptian patients is highly recommended.

Molecular analysis of SMN1 and NAIP genes in Egyptian patients with spinal muscular atrophy.

المجلة: Bratislavske lekarske listy

سنة النشر: 2007

تاريخ النشر: 2007-01-01

The aim of this study is to provide preliminary molecular data on spinal muscular atrophy in Egyptian patients thus facilitating a rapid and conventional molecular assay for accurate diagnosis of SMA.

Background

Childhood spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. It is characterized by symmetrical muscle weakness and atrophy of limbs and trunk. At least four SMA related genes have been identified [survival motor neuron (SMN), neuronal apoptosis inhibitory protein (NAIP), the gene encoding the transcriptional factor p44 and H4F5 gene].

Methods

Homozygous absence of exons 7 and 8 of the SMN1 gene was detected using PCR-SSCP analysis, while NAIP gene deletion was detected using multiplex PCR-agarose gel electrophoresis.

Results

Homozygous absence of SMN1 exons 7 and 8, or exon 7 only, was found in 80% of patients. Of those patients, 45% were also deleted for NAIP exon 5.

Conclusion

The molecular basis of SMA in Egyptian patients has a similar pattern to that reported in most populations, but a larger study is recommended for more comprehensive characterization (Tab. 1, Fig. 2, Ref. 33).

Molecular prenatal diagnosis of autosomal recessive childhood spinal muscular atrophies (SMAs)

المجلة: gene

سنة النشر: 2012

تاريخ النشر: 2012-11-01

Autosomal recessive childhood spinal muscular atrophy (SMAs) is the second most common neuromuscular disorder and a common cause of infant disability and mortality. SMA patients are classified into three clinical types based on age of onset, and severity of symptoms. About 94% of patients have homozygous deletion of exon 7 in survival motor neuron (SMN1) gene. The neuronal apoptosis inhibitory protein (NAIP) gene was found to be more frequently deleted in the severest form of the disease. This study aimed to comment on the implementation of genetic counseling and prenatal diagnosis of SMAs for 85 fetuses from 75 Egyptian couples at risk of having an affected child. The homozygous deletion of exon 7 in SMN1 gene and the deletion of exon 5 of the NAIP gene were detected using PCR-REFLP and multiplex PCR methods respectively. Eighteen fetuses showed homozygous deletion of exon 7 in SMN1 gene and deletion of exon 5 in NAIP gene. In conclusion prenatal diagnosis is an important tool for accurate diagnosis and genetic counseling that help decision making in high risk families.

Screening of GHSR, GHRHR, GH1 genes in isolated growth hormone deficiency disease in Egyptian patients

المجلة: Egyptian Journal of Medical Human Genetics

سنة النشر: 2024

تاريخ النشر: 2024-02-03

Isolated growth hormone deficiency (IGHD) is a hereditary disorder that causes significant short stature. GHD has a reported incidence of 1/4000–1/10,000 births. It is caused by mutations in the major somatotroph axis genes, involving GH1, codes for growth hormone, GHSR, and GHRHR, codes for growth hormone secretagogue receptor and growth hormone-releasing hormone receptor, respectively. Aims of the study The present study aims to examine the clinical phenotype and investigate the genetic etiology of ten Egyptian patients with type I isolated growth hormone insufficiency. Patients and methods Patients recruited for the study were clinically diagnosed by two provocation tests and were subjected to a thorough history, clinical examination, and anthropometric measurements. Sanger sequencing and mutational analysis of the three genes, GH1, GHSR, and GHRHR, was our approach, performed in all enrolled IGHD patients. The variants identified were analyzed using the biological, population, sequence variants, and clinical genetics databases. Prediction of the pathogenicity of the novel variants was done by in silico prediction tools following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results Sanger sequencing revealed a previously reported pathogenic mutation (NM_000823.4: c.1069C > T; p.Arg357Cys) in the GHRHR gene in one patient and a novel frameshift variant (NM_198407.2: c.1043dup; Ser349Leu fs*6) in the GHSR gene in another patient. This is the fourth report highlighting the autosomal dominant inheritance of the GHSR mutation as a cause of isolated growth hormone deficiency. A number of previously reported variants, but of rare frequency, were identified in this study. In our IGHD cases, 90% of the patients were underweight, 50% had anemia, and 80% showed hypovitaminosis D. Conclusion Our findings broaden the mutational spectrum underlying the IGHD in Egyptian patients and point out the importance of mutation screening of the GHSR and GHRHR genes. This study also acknowledges the autosomal dominant mode of inheritance of the GHSR mutation as a cause for dwarfism.