Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder characterized by a progressive weakening and spasticity of the lower limbs. HSP is classified according to the presence or absence of accompanying neurologic problems and by the mode of inheritance. Currently, 17 loci have been linked to the various forms of HSP.To determine the chromosomal location of a gene causing pure autosomal recessive spastic paraplegia.Genotyping using fluorescently labeled microsatellite markers was performed on three affected individuals and three unaffected individuals from a family displaying pure autosomal recessive HSP (ARHSP) and sensorineural deafness. All family members were then included in the analysis to narrow the genetic interval. Candidate genes were screened for the presence of mutations by heteroduplex analysis.The paraplegic trait linked to a 1.8-Mb region of chromosome 13q14 flanked by the FLJ11712 gene and the microsatellite marker D13S270. The deafness did not link to this region and did not cosegregate with the paraplegic trait.The HSP that this family had represents a novel genetic form of pure ARHSP as no other form of HSP (autosomal dominant or recessive) has been linked to chromosome 13.
A consanguineous family of Pakistani ethnicity with two female siblings (22 and 19 years of age), affected by a autosomal recessive Autism Spectrum Disease, was studied by homozygosity mapping and whole Exome Next Generation Sequencing [NGS] of the two affected siblings and one parent to identify the responsible gene and mutation. The disorder is marked by intellectual disability, speech and motor delay, congenital malformations and possibly autism spectrum disorder (ASD). The malformations include microcephaly, microphthalmia, micrognathia and arachnodactyly with hyperextensibility and persistent fetal pads in fingers and toes. The offending gene was mapped to five possible homozygous genomic regions [[6q, 12q, 17p, 20p, 22q], as the family structure did not allow identification of a single interval with a significant LOD score. Comparative analyses of the NGS data for autosomal recessive inheritance and data mining for damaging variants within the homozygosity intervals identified a damaging homozygous c.C1675T / p.R559C mutation in the MYO1A gene, at 12q13.3. The mutation co-segregates with the disease phenotype within the family, is absent in known polymorphism databases and in 400 ethnically matched control chromosomes. Myosins are molecular motors that, upon interaction with actin filaments, utilize energy from ATP hydrolysis to generate mechanical force. The N-terminal motor domain contains both ATP-binding and actin-binding sequences. Following the motor domain is a light-chain-binding 'neck' region containing 1-6 copies of a repeat element, the IQ motif that serves as a binding site for calmodulin and other members of the EF-hand superfamily of calcium-binding proteins. The C terminus has a distinct tail domain that serves in dimerization, membrane binding, protein binding, and/or enzymatic activities and targets each myosin to its particular subcellular location. Heterozygous mutations in MYO1A have been found in patients with sensorineural hearing loss, speculated to cause autosomal dominant sensorineural hearing loss but co-segregation to the phenotype has never been demonstrated. Two rare heterozygous MYO1A mutations [c.G2021A / p.G674D and one in the 3′UTR] have been found in patients with autism but their clinical significance is unknown. The association of MYO1A to autosomal recessive ASD without deafness in this family, elevates the importance of MYO1A both as causative and contributive gene for Autism Spectrum Disease
<b><i>Background/Aims:</i></b> Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP. <b><i>Methods:</i></b> PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations. <b><i>Results:</i></b> No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP. <b><i>Conclusion:</i></b> Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.
We describe a Syrian child with typical features of severe cystic fibrosis (CF) phenotype and a positive sweat test. DNA analysis confirmed homozygosity for the Δ F508 mutation on chromosome 7. This report stresses the need to draw attention to and consider CF in Arab populations. The frequency and distribution of Δ F508 in the Middle East are reviewed.
A descriptive study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Saudi Arabian cystic fibrosis (CF) population in relation to clinical presentation and demographic and ethnic origin. During the period October 1992 to September 1997, 70 patients from 46 families were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. Twelve mutations were identified in 34 families, which constitutes 70% of the CF alleles in the study group. Pancreatic insufficiency (PI) was found in the following mutations: 1548delG in exon 10 (15%) which occurred mainly in native Saudi patients in the central province; 3120 + 1G-->A in intron 16 (10%) and H139L in exon 4 (7%), found mainly in native Saudis from the eastern province; delta F508 mutation (13%) which occurred mainly in expatriates of Middle Eastern origin from different provinces; L117X in exon 19 (2%); G115X in exon 4 (2%); 711 + 1G-->A in intron 5 (2%); N 1303K in exon 21 (2%) and 425del42 in exon 4 (1%); I1234V in exon 19 (13%) with a predominance of nasal polyps and a variable degree of PI and lung disease; R553X in exon 11 (1%), with electrolyte imbalance; and S549R in 11 (2%) with pancreatic sufficiency and minimal pulmonary disease. The clinical picture did not differ significantly between patients of different ethnic origins with the same CFTR mutation.
Lecture 27 Genes control biological systems such as muscle, cartilage and bone formation, muscle energy production and metabolism (mitochondriogenesis, lactic acid removal), blood and tissue oxygenation (erythropoiesis, angiogenesis, vasodilatation) all essential in Athletics and Sports. DNA sequence variations in these genes confer genetic advantages that can be exploited and genetic ‘barriers’ that could be overcome to achieve optimal athletic performance. The four ‘P's of Predictive Genomics (Personalization, Prediction, Prevention, Participation) are not only applicable but rather essential in athletics. Predictive genomic profiling for athletics reveals genetic variations that determine suitability for sports requiring either endurance or strength and speed, determine vulnerability to sports-related traumas as well as individualised nutritional requirements. Knowledge of genetic ‘suitability’ in respect to endurance capacity or strength and speed would lead to appropriate sport and athletic activity selection. Knowledge of genetic advantages and barriers would ‘direct’ an individualised training programme and nutritional plan and supplementation to achieving optimal performance, overcome the ‘pain barriers’ that results from intense exercise and pressure under competition with minimum waste of time and energy and avoidance of health risks (hypertension, cardiovascular disease, inflammation and injuries in tendons and bones) related to exercise, training and competition. Genetic ‘profiling’ for Athletics and Sports performance is an essential tool for proper Athletic activity and Sport selection as well as for the formulation of Individualized and Personalized training and nutritional programmes for optimising health and performance for the athlete.
Introduction: Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. Methods: We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays. Next, we employed Next Generation Sequencing (NGS) to identify de novo or inherited variants contributing to the ASD etiology and its associated comorbid conditions in families with complete trios (affected child and the parents). Results: Our analysis revealed 16 CNV regions located in genomic regions implicated in ASD. The analysis of the 88 ASD cases identified 41 genes in 39 ASD subjects with de novo (n = 24) or inherited variants (n = 22). We identified three novel de novo variants in new candidate genes for ASD ( DTX4 , ARMC6 , and B3GNT3 ). Also, we have identified 15 de novo variants in genes that were previously implicated in ASD or related neurodevelopmental disorders ( PHF21A , WASF1 , TCF20 , DEAF1 , MED13 , CREBBP , KDM6B, SMURF1 , ADNP , CACNA1G , MYT1L , KIF13B , GRIA2 , CHM , and KCNK9 ). Additionally, we defined eight novel recessive variants ( RYR2 , DNAH3 , TSPYL2 , UPF3B KDM5C , LYST , and WNK3 ), four of which were X-linked. Conclusion: Despite the ASD multifactorial etiology that hinders ASD genetic risk discovery, the number of identified novel or known putative ASD genetic variants was appreciable. Nevertheless, this study represents the first comprehensive characterization of ASD genetic risk in Qatar's Middle Eastern population.
Various chromosomal anomalies including small supernumerary marker chromosome (sSMC) and Uniparental disomy (UPD) have been described in association with intellectual disability and autism spectrum disorder. Based on our reported findings, we recommend that patients with sSMC(8) be evaluated for autism spectrum disorder (ASD) for early institution of therapy. In the presence of an identifiable sSMC, exploration of UPD is also recommended to further investigate the role of chromosome 8 UPD in ASD.
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