Spectrum of genetic variants in bilateral sensorineural hearing loss.

Background: Hearing loss (HL) is an impairment of auditory function with identified genetic forms that can be syndromic (30%) or non-syndromic (70%). HL is genetically heterogeneous, with more than 1,000 variants across 150 causative genes identified to date. The genetic diagnostic rate varies significantly depending on the population being tested. Countries with a considerably high rate of consanguinity provide a unique resource for studying rare forms of recessive HL. In this study, we identified genetic variants associated with bilateral sensorineural HL (SNHL) using whole-exome sequencing (WES) in 11 families residing in the United Arab Emirates (UAE). Results: We established the molecular diagnosis in six probands, with six different pathogenic or likely pathogenic variants in the genes MYO15A, SLC26A4, and GJB2. One novel nonsense variant, MYO15A:p.Tyr1962Ter*, was identified in a homozygous state in one family, which has not been reported in any public database. SLC26A4 and GJB2 were found to be the most frequently associated genes in this study. In addition, six variants of uncertain significance (VUS) were detected in five probands in the genes CDH23, COL11A1, ADGRV1, NLRP3, and GDF6. In total, 12 variants were observed in eight genes. Among these variants, eight missense variants (66.7%), three nonsense variants (25.0%), and one frameshift (8.3%) were identified. The overall diagnostic rate of this study was 54.5%. Approximately 45.5% of the patients in this study came from consanguineous families. Conclusion: Understanding the genetic basis of HL provides insight for the clinical diagnosis of hearing impairment cases through the utilization of next-generation sequencing (NGS). Our findings contribute to the knowledge of the heterogeneous genetic profile of HL, especially in a population with a high rate of consanguineous marriage in the Arab population.

Case report: Birk-Landau-Perez syndrome linked to the SLC30A9 gene-identification of additional cases and expansion of the phenotypic spectrum.

Birk-Landau-Perez syndrome (BILAPES) is an autosomal recessive cerebro-renal syndrome associated with genetic defects in the SLC30A9 gene, initially reported in 2017 in six individuals belonging to a large Bedouin kindred. The SLC30A9 gene encodes a putative mitochondrial zinc transporter with ubiquitous expression, the highest found in the brain, kidney, and skeletal muscle. Since the first report, only one additional affected patient has been described, but there were some inconsistencies, such as hearing loss, failure to thrive, and neuroimaging findings between the clinical presentation of the disease in the Bedouin family and the second patient. Here, we present two more patients from a consanguineous Middle Eastern family with features of chronic kidney disease, neurodevelopmental regression, ataxia, hearing loss, and eye abnormalities, which were largely consistent with BILAPES. Whole-exome sequencing detected a homozygous in-frame deletion c.1049_1051delCAG (p.Ala350del) in the SLC30A9 gene, which was the same variant detected in the patients from the primary literature report and the variant segregated with disease in the family. However, in the patients described here, brain MRI showed cerebellar atrophy, which was not a cardinal feature of the syndrome from the primary report. Our findings provide further evidence for SLC30A9-associated BILAPES and contribute to defining the clinical spectrum.

Novel compound heterozygous variants (c.971delA/c.542C > T) in SLC1A4 causes spastic tetraplegia, thin corpus callosum, and progressive microcephaly: a case report and mutational analysis.

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) are linked to SLC1A4 genetic variants since the first reported case in 2015. SLC1A4 encodes for the neutral amino acid transporter ASCT1 which is involved in the transportation of serine between astrocytes and neurons. Although most of the reported cases are of Ashkenazi Jewish ancestry, SPATCCM has also been reported in Irish, Italian, Czech, Palestinian, and Pakistani ethnicities. Herein, we report two Pakistani male siblings from a non-consanguineous marriage presented with global developmental delay associated with spastic quadriplegia, microcephaly, and infantile spasm. Since infancy, both siblings suffered from microcephaly with brain MRI demonstrating generalized atrophy of the frontal, temporal, and parietal lobes with a prominence of the subarachnoid spaces, widening of the Sylvian fissures, and enlargement of the ventricular system not compatible with the chronological age of both patients associated with thinning of the corpus callosum. Whole-exome sequencing of both affected brothers revealed novel compound heterozygous variants in the SLC1A4 gene (NM_003038) segregating from their parents. The maternal c.971delA (p.N324Tfs*29) deletion variant disturbs the transcript reading frame leading to the generation of a premature stop codon and its subsequent degradation by nonsense-mediated mRNA decay as detected through expression analysis. The paternal c.542C > T (p.S181F) missense variant was predicted deleterious via multiple in silico prediction tools as the amino acid substitution is speculated to affect the overall ASCT1 structural confirmation due to the loss of an H-bond at the core of the protein at this position which might affect its function as concluded from the simulation analysis. The presented cases expand the genetic and clinical spectrum of ASCT1 deficiency and support the importance of including SLC1A4 gene screening in infants with unexplained global neurodevelopmental delay regardless of ethnicity.

Lupus nephritis: A focus on the United Arab Emirates and the potential role of genetics.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), characterized by chronic and progressive inflammation of the kidneys. As with many other autoimmune diseases, LN is a multifactorial disease caused by genetic and environmental factors. Globally, LN can affect around 60% of SLE patients, and it was observed to be less frequent and severe in Caucasian patients compared to other ethnic groups, including Arabs. Data on LN in the United Arab Emirates (UAE) are scattered and scarce in literature. Nevertheless, LN is common, occurring in around 43%-55% of SLE patients in the UAE. Anecdotally, the demographics and clinical features of SLE in the UAE have been distinct. However, the paucity of supporting literature makes it difficult to draw meaningful conclusions. Over the past two decades, there have been improvements in understanding the pathogenesis of LN; however, many cellular and molecular mechanisms which are implicated in the disease development and progression remain ambiguous. Investigating the clinical, pathological, and genetic characteristics of LN in different cohorts of patients is of importance for a better understanding of its pathogenesis, and thus improving its outcome. As a result, we acknowledge the need for large-scale epidemiological, clinical, and genetic investigation of LN cohorts in the UAE and surrounding regions.