Revisiting Exome Data Identified Missed Splice Site Variant of the Asparagine Synthetase ( ASNS ) Gene.

Next-generation sequencing, such as whole-exome sequencing (WES), is increasingly used in the study of Mendelian disorders, yet many are reported as "negative." Inappropriate variant annotation and filtering steps are reasons for missing the molecular diagnosis. Noncoding variants, including splicing mutations, are examples of variants that can be overlooked. Herein, we report a family of four affected newborns, and all presented with severe congenital microcephaly. Initial research WES analysis identified a damaging homozygous variant in NME1 gene as a possible cause of primary microcephaly phenotype in these patients. However, reanalysis of the exome data uncovered a biallelic splice site variant in asparagine synthetase gene which seems to be the possible cause of the phenotype in these patients. This study highlights the importance of revisiting the exome data and the issue of "negative" exome and the afterward approaches to identify and prove new candidate genes.

The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.

Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.

Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

Estimate of the HOMA-IR Cut-off Value for Identifying Subjects at Risk of Insulin Resistance Using a Machine Learning Approach.

OBJECTIVES: This study describes an unsupervised machine learning approach used to estimate the homeostatic model assessment-insulin resistance (HOMA-IR) cut-off for identifying subjects at risk of IR in a given ethnic group based on the clinical data of a representative sample. METHODS: The approach was applied to analyse the clinical data of individuals with Arab ancestors, which was obtained from a family study conducted in Nizwa, Oman, between January 2000 and December 2004. First, HOMA-IR-correlated variables were identified to which a clustering algorithm was applied. Two clusters having the smallest overlap in their HOMA-IR values were retrieved. These clusters represented the samples of two populations, which are insulin-sensitive subjects and individuals at risk of IR. The cut-off value was estimated from intersections of the Gaussian functions, thereby modelling the HOMA-IR distributions of these populations. RESULTS: A HOMA-IR cut-off value of 1.62 ± 0.06 was identified. The validity of this cut-off was demonstrated by showing the following: 1) that the clinical characteristics of the identified groups matched the published research findings regarding IR; 2) that a strong relationship exists between the segmentations resulting from the proposed cut-off and those resulting from the two-hour glucose cut-off recommended by the World Health Organization for detecting prediabetes. Finally, the method was also able to identify the cut-off values for similar problems (e.g. fasting sugar cut-off for prediabetes). CONCLUSION: The proposed method defines a HOMA-IR cut-off value for detecting individuals at risk of IR. Such methods can identify high-risk individuals at an early stage, which may prevent or delay the onset of chronic diseases such as type 2 diabetes.

Biallelic PTRHD1 Frameshift Variants Associated with Intellectual Disability, Spasticity, and Parkinsonism.

BACKGROUND: PTRHD1 was proposed as a disease-causing gene of intellectual disability, spasticity, and parkinsonism. OBJECTIVES: To characterize the clinical phenotype and the molecular cause of intellectual disability in four affected individuals of a consanguineous family. METHODS: Clinical evaluation, whole-exome sequencing, Sanger sequencing, reverse transcription polymerase chain reaction (PCR), real-time PCR, immunoblot, and isoelectric focusing. RESULTS: A homozygous 28-nucleotide frameshift deletion introducing a premature stop codon in the PTRHD1 exon 1 was identified in the four affected members. We further confirmed the apparent transcript escape of the nonsense-mediated messenger RNA (mRNA) decay pathway. Real-time PCR showed that mRNA expression of the mutant PTRHD1 is higher compared to the wild-type. Western blotting and isoelectric focusing identified a truncated, but stable mutant PTRHD1 protein expressed in the patient's primary cells. CONCLUSIONS: We provide further evidence that PTRHD1 mutations are associated with autosomal-recessive childhood-onset intellectual disability associated with spasticity and parkinsonism.

Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.

INTRODUCTION AND OBJECTIVE: Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS: The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS: A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS: In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.

Heritability and genetic correlations of obesity indices with ambulatory and office beat-to-beat blood pressure in the Oman Family Study.

OBJECTIVE: To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP. METHODS: We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n = 1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10 min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age, sex, age-sex and age--sex interactions. RESULTS: Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8--21.4% for sleeping time, 32.1--40.4% for 24-h and 22--24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14--0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16--0.50; rE: 0.01--0.31). CONCLUSION: The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Heritability and genetic and environmental correlations of heart rate variability and baroreceptor reflex sensitivity with ambulatory and beat-to-beat blood pressure.

This family study from Oman (n = 1231) explored the heritability and genetic and environmental correlations of heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS) with ambulatory and beat-to-beat blood pressure (BP). Ambulatory BP was measured for 24 hours to calculate mean values for daytime and sleep separately. Time and frequency domain HRV indices, BRS, office beat-to-beat BP, and heart rate (HR) were measured for 10 minutes at rest. SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, their interactions and BMI. Heritability of SBP and DBP ranged from 16.8% to 40.4% for daytime, sleeping, 24-hour and office beat-to-beat measurements. HR and BRS showed a heritability of 31.9% and 20.6%, respectively, and for HRV indices heritability ranged from 11.1% to 20.5%. All HRV measurements and BRS were found to be negatively correlated with BP, but phenotypic correlation coefficients were relatively weak; HR was positively correlated with BP. None of the genetic correlations were statistically significant while environmental factors explained most of the correlations for all HRV indices with BP. Our study found consistent but weak correlations among HRV, HR, BRS and ambulatory/office beat-to-beat BP. However, environmental rather than genetic factors contributed most to those correlations.

Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.

INTRODUCTION: Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). METHODS: Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. RESULTS: Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. CONCLUSION: Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Association of gene variants with susceptibility to type 2 diabetes among Omanis.

AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis. METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012. RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10(-6), OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 ×10(-7), OR = 2.4), [among males (n = 234, P = 1.2 × 10(-4), OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)]. CONCLUSION: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.

The Effect of Residing Altitude on Levels of High-Density Lipoprotein Cholesterol: A Pilot Study From the Omani Arab Population.

Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes.

Consanguinity, endogamy and inborn errors of metabolism in Oman: a cross-sectional study.

The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients.

Utility of large consanguineous family-based model for investigating the genetics of type 2 diabetes mellitus.

OBJECTIVES: This study examined the utility of a family-based model for replicating the results of genome-wide association studies (GWAS) of type 2 diabetes (T2D). METHODS AND RESULTS: In a total of 232 members of a large consanguineous Omani Arab pedigree (age: 16-80years), there were 27 diabetics and 50 prediabetics (17 with impaired fasting glucose and 33 with impaired glucose tolerance). All 232 individuals underwent anthropometric and biochemical investigations and genotyped for 14 known common gene variants of modest effect on T2D risk. Power analysis at a LOD score of 3, gave 80% power to locate a single specific locus that accounts for 52% of the total phenotypic variation. Measured genotype analysis (MGA) was used to determine heritability of various quantitative traits (QTs) which ranged 25-56%. Using MGA, some common gene variants were found to have little (<5%) but significant impact on the heritability of T2D related QTs [KCNJ11 (rs5219), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.031]; [FTO (rs8050136), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05]. Sib-TDT analysis showed that some gene variants were significantly associated with T2D risk but didn't reach the level of significance after Bonferroni correction [KCNJ11 (rs5219), p=0.047] and [CAPN10 (rs41266971), p=0.035]. CONCLUSION: We have demonstrated that, in principle, a family-based model with minor limitations could be used to replicate some of the results of large GWAS case-control studies. This model could successfully be applied for the future discovery, by deep sequencing, of rare gene variants.

Impaired Fasting Glucose in Omani Adults with no Family History of Type 2 Diabetes.

OBJECTIVES: The aim of this study was to estimate the prevalence of impaired fasting glucose (IFG) among Omani adults with no family history (FH) of diabetes and to investigate the factors behind the risk of developing type 2 diabetes (T2D), while excluding a FH of diabetes. METHODS: A total of 1,182 Omani adults, aged ≥40 years, visited the Family Medicine & Community Health Clinic at Sultan Qaboos University Hospital, Oman, on days other than the Diabetes Clinic days, from July 2010 to July 2011. The subjects were interviewed and asked if they had T2D or a FH of T2D. RESULTS: Only 191 (16%) reported no personal history of T2D or FH of the disease. Of these, anthropometric and biochemical data was complete in 159 subjects. Of these a total of 42 (26%) had IFG according to the American Diabetes Association criteria. Body mass index, fasting insulin, haemoglobin A1C and blood pressure (BP), were significantly higher among individuals with IFG (P <0.01, P <0.05, P <0.01 and P <0.01, respectively). In addition, fasting insulin, BP and serum lipid profile were correlated with obesity indices (P <0.05). Obesity indices were strongly associated with the risk of IFG among Omanis, with waist circumference being the strongest predictor. CONCLUSION: Despite claiming no FH of diabetes, a large number of Omani adults in this study had a high risk of developing diabetes. This is possibly due to environmental factors and endogamy. The high prevalence of obesity combined with genetically susceptible individuals is a warning that diabetes could be a future epidemic in Oman.

Familial Clustering of Type 2 Diabetes among Omanis.

OBJECTIVE: The aim of this study was to screen Omani individuals for the familial aggregation of type 2 diabetes mellitus. METHODS: A random cohort of 1182 Omani individuals visiting the Family Medicine Clinic at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, for regular medical checkup, aged ≥40 years, were sampled. Patients were categorized into three groups: (1) individuals who claim not to have diabetes and had no family history of diabetes; (2) individuals who claim not to have diabetes but had family history of diabetes; (3) individuals with diabetes. Only 16% of these Omani individuals had no diabetes and no family history of diabetes. Another separate random cohort of 234 Omani type 2 diabetes mellitus patients, from the Diabetes Clinic at SQUH, were interviewed and questioned about their family history of type 2 diabetes mellitus. RESULTS: Ninety five percent of the patients had a family history of diabetes. Eighty percent had first degree relatives with diabetes and 46% had second degree relatives with diabetes. At least one parent with diabetes was reported among 55% of these diabetics, while maternal diabetes (55%) was found to be higher than paternal diabetes (47%). However, only 15% had both parents with diabetes. Furthermore, almost half of the 234 diabetics were having at least one of the following relatives with diabetes: brother, sister, aunt or an uncle. CONCLUSION: The findings of this study confirm familial aggregation of diabetes among the Omani population. Compared to other populations, familial aggregation of type 2 diabetes mellitus among Omanis is relatively very high, and is perhaps due to the very high degree of consanguinity among Omanis. Since almost everyone seems to have a genetic predisposition to diabetes, the dramatic lifestyle changes over the past 25 years, could tip the population into an epidemic of type 2 diabetes mellitus.

Transglutaminase-1 mutations in Omani families with lamellar ichthyosis.

OBJECTIVE: To determine the molecular basis of familial ichthyosis in three Omani families. SUBJECTS AND METHODS: Nine patients from three consanguineous families, A, B, and C, were born with typical features of lamellar ichthyosis subtype including collodion membrane and maintained ectropion, and epidermal scaling through their childhood. The 4 patients from family B had more severe symptoms requiring neonatal critical care and subsequent regular treatment with emollients, eye lubricants, and low-dose acitretin. DNA was extracted from peripheral blood by standard methods. The samples were initially genotyped to screen known loci linked to recessive ichthyosis on chromosomes 2q33-32 (ABCA12), 14q11 (TGM1), and 19p12-q12 using commercially supplied polymorphic fluorescent microsatellite markers. TGM1 was analyzed by direct sequencing for disease-associated mutations. RESULTS: Two known pathogenic mutations in TGM1 were detected: p.Gly278Arg in families A and B and p.Arg396His in family C. These two mutations were segregating in an autosomal recessive mode of inheritance. CONCLUSION: Two known pathogenic TGM1 mutations were detected in three large consanguineous Omani families with lamellar ichthyosis. This study confirmed the geographic distribution of known mutations to an apparently unrelated population.

Pelizaeus-Merzbacher-Like Disease in a Family With Variable Phenotype and a Novel Splicing GJC2 Mutation.

Pelizaeus-Merzbacher-like disease is an autosomal recessive disorder characterized by neonatal nystagmus, ataxia, progressive spasticity, and development delay and is rarely caused by GJC2 mutations. We report 7 patients from a large consanguineous family who had variable severity of Pelizaeus-Merzbacher-like disease. The 3 youngest of branch A were bedridden by their first year because of permanent scissoring of their legs and had severe frontal lobe epilepsy. The single patient from branch B was the least affected, being able to walk until 12 years of age and had no epilepsy. Brain magnetic resonance imaging (MRI) showed hypomyelination. The patients had a novel canonical splicing GJC2 c.-20+1G>C mutation with a predicted loss of the coding connexin 47 protein. The exceptionally large number of patients in this unique family enabled to describe the intrafamilial variability of Pelizaeus-Merzbacher-like disease. The predicted functional loss of connexin 47 might be associated with a severe form of Pelizaeus-Merzbacher-like disease.

Clinical and molecular analysis of isovaleric acidemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene.

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD). Accumulation of isovaleryl-CoA derivatives to toxic levels results in clinical symptoms of the disease. Here, we investigate the clinical and molecular features of Arab patients with IVA. Patients from five unrelated families were evaluated clinically and for defects in the IVD gene. Four novel mutations (p.F382fs, p.R392H, p.R395Q and p.E408K) have been identified with p.R395Q occurring in two families. In addition, molecular modeling of the identified missense mutations predicted their damaging effects on the protein and computational analysis of the p.F382fs mutation predicted the disruption of a 3' splicing site resulting in inactive or unstable gene product. Furthermore, we found an unusual case of a 17 years old female homozygous for the p.R392H mutation with no clinical symptoms. Our results illustrate a heterogeneous mutation spectrum and clinical presentation in the relatively small UAE population.

Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation.

Hyperekplexia is characterized by neonatal hypertonia and exaggerated startle reflex in response to loud noise or tactile stimuli. Mutations in patients with hyperekplexia were evident in several genes encoding proteins involved in glycinergic neurotransmission, i.e., glycine receptor α and ß subunits, collybistin, gephyrin, and glycine transporter 2. We clinically and genetically characterized two large, unrelated consanguineous families with hyperekplexia. Affected members of the two families manifested hyperekplexia with mild mental retardation. Patients exhibited a novel homozygote c.593G>C missense mutation in GLRA1, resulting in amino acid substitution p.W170S in the corresponding mature glycine receptor α1 subunit. This mutation was absent in 400 randomly selected chromosomes in the same population. In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.

Identification of mutations underlying 20 inborn errors of metabolism in the United Arab Emirates population.

Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders.