Abstract
BackgroundAmong 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 presentationWe 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0642-z) contains supplementary material, which is available to authorized users.
Highlights
Among the 21 annotated genes at Xq22.2, proteolipid protein 1 (PLP1) is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability
We hypothesize that glycine receptor (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
The centromeric deletion breakpoint resides in the intergenic region 1 between transcription elongation factor a-like 1 (TCEAL1) and transcription elongation factor a-like 3 (TCEAL3), while the telomeric breakpoint was found to reside in the intergenic region 2 between GLRA4 and PLP1 (Figs. 2 and 3b)
Summary
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. 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. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084′s family, 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. More than 100 ID genes residing on the X-chromosome have been identified, and it is thought that more XLID genes are yet to be discovered, in X-linked families where the genes map to new loci [2, 8,9,10].
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