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.

Radiative transfer of acoustic waves in continuous complex media: Beyond the Helmholtz equation.

Heterogeneity can be accounted for by a random potential in the wave equation. For acoustic waves in a fluid with fluctuations of both density and compressibility (as well as for electromagnetic waves in a medium with fluctuation of both permittivity and permeability) the random potential entails a scalar and an operator contribution. For simplicity, the latter is usually overlooked in multiple scattering theory: whatever the type of waves, this simplification amounts to considering the Helmholtz equation with a sound speed c depending on position r. In this work, a radiative transfer equation is derived from the wave equation, in order to study energy transport through a multiple scattering medium. In particular, the influence of the operator term on various transport parameters is studied, based on the diagrammatic approach of multiple scattering. Analytical results are obtained for fundamental quantities of transport theory such as the transport mean-free path ℓ^{*}, scattering phase function f, and anisotropy factor g. Discarding the operator term in the wave equation is shown to have a significant impact on f and g, yet limited to the low-frequency regime, i.e., when the correlation length of the disorder ℓ_{c} is smaller than or comparable to the wavelength λ. More surprisingly, discarding the operator part has a significant impact on the transport mean-free path ℓ^{*} whatever the frequency regime. When the scalar and operator terms have identical amplitudes, the discrepancy on the transport mean-free path is around 300% in the low-frequency regime, and still above 30% for ℓ_{c}/λ=10^{3} no matter how weak fluctuations of the disorder are. Analytical results are supported by numerical simulations of the wave equation and Monte Carlo simulations.

Scattering mean free path in continuous complex media: beyond the Helmholtz equation.

We present theoretical calculations of the ensemble-averaged (or effective or coherent) wave field propagating in a heterogeneous medium considered as one realization of a random process. In the literature, it is usually assumed that heterogeneity can be accounted for by a random scalar function of the space coordinates, termed the potential. Physically, this amounts to replacing the constant wave speed in Helmholtz' equation by a space-dependent speed. In the case of acoustic waves, we show that this approach leads to incorrect results for the scattering mean free path, no matter how weak the fluctuations. The detailed calculation of the coherent wave field must take into account both a scalar and an operator part in the random potential. When both terms have identical amplitudes, the correct value for the scattering mean free paths is shown to be more than 4 times smaller (13/3, precisely) in the low-frequency limit, whatever the shape of the correlation function. Based on the diagrammatic approach of multiple scattering, theoretical results are obtained for the self-energy and mean free path within Bourret's and on-shell approximations. They are confirmed by numerical experiments.