Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families.

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability.

BACKGROUND: 1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family. CASE PRESENTATION: Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced. CONCLUSION: From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies.

A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.

BACKGROUND: Among the 21 annotated genes at Xq22.2, PLP1 is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability. Using an atypical microdeletion, which does not encompass PLP1, we implicate a novel gene GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies. CASE PRESENTATION: We report a female patient (DGDP084) with a de novo Xq22.2 microdeletion of at least 110 kb presenting with intellectual disability, motor delay, behavioral problems and craniofacial anomalies. While her phenotypic features such as cognitive impairment and motor delay show overlap with Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations at Xq22.2, this gene is not included in our patient's microdeletion and is not dysregulated by a position effect. Because the microdeletion encompasses only three genes, GLRA4, MORF4L2 and TCEAL1, we investigated their expression levels in various tissues by RT-qPCR and found that all three genes were highly expressed in whole human brain, fetal brain, cerebellum and hippocampus. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084's family, however, only GLRA4 transcripts were reduced in the female patient compared to her healthy mother. This suggests that GLRA4 is the plausible candidate gene for cognitive impairment, behavioral problems and craniofacial anomalies observed in DGDP084. Importantly, glycine receptors mediate inhibitory synaptic transmission in the brain stem as well as the spinal cord, and are known to be involved in syndromic intellectual disability. CONCLUSION: We hypothesize that GLRA4 is involved in intellectual disability, behavioral problems and craniofacial anomalies as the second gene identified for X-linked syndromic intellectual disability at Xq22.2. Additional point mutations or intragenic deletions of GLRA4 as well as functional studies are needed to further validate our hypothesis.