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.

Uptake of prenatal genetic diagnosis and termination of pregnancy by Omani Muslim families at risk of genetic disorders: experience over a 9-year period.

Studies on the acceptance of prenatal diagnosis and termination of pregnancy for single gene disorders within Islamic societies in the Middle East are limited. A few have examined the attitudes toward pregnancy termination for fetal indications, but a dearth of published data exists on actual behavior and uptake. This study reports on all prenatal diagnosis requests for single gene disorders, from the Sultanate of Oman, over 9 years. A retrospective study was conducted during which the medical records of all women who performed prenatal diagnoses for single gene disorders were reviewed. A total of 148 invasive procedures were performed for 114 families. The total number of yearly requests for prenatal diagnosis increased exponentially from three in 2012 to 21 in 2020. Sixty-four different diagnoses were tested for with the majority being autosomal recessive in nature. Seventy-one percent (28/39) of cases where an affected pregnancy was identified were terminated. Fifty-two of the 114 women (45.6%) repeated prenatal diagnosis in a future pregnancy. Seventy-two couples (63%) were consanguineous parents related as second cousins or closer. The majority of tests performed were for couples from Muscat (27%), Albatinah (27%), and Alsharqiya (20.3%) governorates in Oman. The findings of this study provide evidence that prenatal diagnosis is an acceptable reproductive option to prevent the occurrence of genetic disorders that meet termination eligibility criteria as outlined by the Islamic Jurisprudence (Fiqh) Council Fatwa, among Omani Muslim couples.

Biallelic loss-of-function variants of GFRA1 cause lethal bilateral renal agenesis.

Bilateral renal agenesis belongs to a group of perinatal lethal renal diseases. To date, pathogenic variants in three genes (ITGA8, GREB1L, and FGF20) have been shown to cause renal agenesis in humans. Recently GFRA1 has been linked to a phenotype consistent with a nonsyndromic form of bilateral renal agenesis. GFRA1 encodes a member of the glial cell line-derived neurotrophic factor receptor family of proteins. The receptor on the Wolffian duct regulates ureteric bud outgrowth in developing a functional renal system. We report on four additional affected neonates from a consanguineous family who presented with a similar lethal phenotype whereby whole exome sequencing identified a homozygous deleterious sequence variant in GFRA1 (NM_005264.8:c.628G > T:p.[Gly210Ter]). The current study represents a second confirmation report on the causal association of GFRA1 pathogenic variants with lethal nonsyndromic bilateral renal agenesis in humans.

The experience of Preimplantation Genetic Testing (PGT) among Muslim couples in Oman in the Middle East.

Preimplantation genetic testing (PGT) is an alternative reproductive technology integrated with in vitro fertilization (IVF). It is a well-established technique offering a reproductive option for families at a high risk of transmitting a genetic disorder, allowing them to avoid making a decision about termination of an affected pregnancy (TOP). In Arab communities and particularly in Oman, where TOP is not favored under the majority of implemented Muslim law, termination of pregnancy for fetal indications is not always possible. As these communities are in favor of consanguineous marriage, they are at increased risk of serious and lethal autosomal recessive conditions, and as a result, PGT is a feasible option as a TOP decision can be avoided. However, undergoing PGT is relatively new in the Arab Muslim countries and Omani patients have only recently had access to the service. This qualitative study utilized a phenomenological approach to explore the experience of Omani families who had selected to undergo PGT as a means of reducing the risk of having a child affected with a genetic disorder. Fourteen participants from eight families who underwent PGT were interviewed. Data collected were analyzed using thematic analysis. The research identified four main themes: Anxiously waiting 'Taraqub'; Unforeseen; Secrecy; and Me and My Partner. The findings of the research have provided insight into the PGT experiences of Omani families. Unique cultural and religious perspectives should be considered when counseling Omani Muslim couples.

Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset.

Failure to thrive (FTT) causes significant morbidity, often without clear etiologies. Six individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Standard diagnostic work up did not ascertain an etiology. Autozygosity mapping and whole exome sequencing identified homozygosity for a novel genetic variant of the long chain fatty acyl-CoA synthetase 5 (ACSL5) shared among the affected individuals (NM_203379.1:c.1358C>A:p.(Thr453Lys)). Autosomal recessive genotype-phenotype segregation was confirmed by Sanger sequencing. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss-of-function mutation without any remaining activity. ACSL5 belongs to an essential enzyme family required for lipid metabolism and is known to contribute the major activity in the mouse intestine. Based on the function of ACSL5 in intestinal long chain fatty acid metabolism and the gastroenterological symptoms, affected individuals were treated with total parenteral nutrition or medium-chain triglyceride-based formula restricted in long-chain triglycerides. The patients responded well and follow up suggests that treatment is only required during early life.

Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience.

OBJECTIVE: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. STUDY DESIGN: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. RESULTS: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). CONCLUSION: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease.

Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status.

Identification of prognosis markers in pediatric high-risk acute lymphoblastic leukemia.

Gene expression profiling may improve the understanding of the biology behind relapse in pediatric acute lymphoblastic leukemia. Using suppression subtractive hybridization (SSH), cDNA concatenated sequencing (CCS), and reverse transcriptase real-time quantitative polymerase chain reaction (RT-RQ-PCR) on high-risk patient samples with nondeterminant chromosomal translocation, the authors identified 3 genes that were significantly overexpressed in the nonrelapsed patients: the calcium/calmodulin-dependent serine protein kinase (CASK), subunit 2 of the cofactor required for SP1 transcriptional activation (CRSP2), and granzyme K (GZMK). The level of expression of these biomarkers may help identify patients with potentially good prognosis within a group otherwise at high risk of relapse.

Trinucleotide repeat analysis of spinocerebellar ataxia patients in Oman.

OBJECTIVE: To explore the profile of cytosine/adenine/guanine (CAG) repeat expansion in Omani spinocerebellar ataxia (SCA) patients. METHODS: Ten SCA patients attending the Sultan Qaboos University Hospital Neurologic clinics, Al-Khoud, Oman in the 3 years starting from January 2000 were recruited for this study. Genomic DNA was extracted from peripheral blood samples and CAG repeat expansion analysis was carried out by polymerase chain reaction and sequencing, when required. RESULTS: The CAG triplet repeats leading to polyglutamine expansion and neurodegeneration are seen in spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. By using primers for SCA 1, 2, 3 and 7, we found the repeats were in the normal range and triplet repeats do not seem to be a common cause for ataxia in Oman. CONCLUSION: Spinocerebellar ataxia in Oman has the normal range of CAG repeats for the commonly found SCA1, SCA2, SCA3 and SCA7.