Compound heterozygous microdeletion of chromosome 15q13.3 region in a child with hypotonia, impaired vision, and global developmental delay

Abstract

Homozygous or compound heterozygous microdeletion of 15q13.3 region is a rare but clinically recognizable syndrome manifested by profound intellectual disability, muscular hypotonia, intractable seizures, and visual impairment. We identified a compound heterozygous 15q13.3 microdeletion in a 23-month-old girl with global developmental delay, generalized muscular hypotonia, and visual dysfunction. The larger deletion was approximately 1.28 Mb in size and contained seven genes including the TRPM1 and CHRNA7, while the smaller deletion was estimated to be 410 Kb in size and contained only CHRNA7. Compound heterozygous 15q13.3 microdeletion is extremely rare and to the best of our knowledge only two such patients have been reported in literature thus far. The findings in our patient suggest that the pathogenesis of visual dysfunction, which is a consistent finding in homozygous/compound heterozygous 15q13.3 microdeletion depends upon the size of microdeletion. Homozygous loss of TRPM1 likely causes retinal dysfunction while homozygous loss of CHRNA7 alone may lead to visual impairment by cortical mechanisms.

Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

“…also observed that reported cases carrying a minimal microdeletion in the region encompassing the single CHRNA7 gene,14,15 also included an intergenic region containing regulatory elements potentially accounting for OTUD7A expression. This suggests that the phenotypes observed in patients carrying CHRNA7 deletions may not have resulted from CHRNA7 dysfunction, but instead from an aberrant OTUD7A expression and downstream activity of the encoded deubiquitinase.…”

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature

“…Three additional cases with 15q13.3 homozygous deletions reported in 2014 provide some support for the likelihood that biallelic loss of TRPM1 may be associated with characteristic retinal dysfunction. 20,27 However, cases with deletions showing biallelic loss of only CHRNA7 also have visual impairment, thus limiting definitive conclusions. 20,27 With respect to placenta previa, there are studies of embryo implantation in a null mouse model implicating the 15q13.3 region gene KLF13, as well as KLF9, a related gene located at 9q13.…”

“…20,27 However, cases with deletions showing biallelic loss of only CHRNA7 also have visual impairment, thus limiting definitive conclusions. 20,27 With respect to placenta previa, there are studies of embryo implantation in a null mouse model implicating the 15q13.3 region gene KLF13, as well as KLF9, a related gene located at 9q13. 35 These genes encode members of the Krüppel-like family of transcription factors, which are needed to maintain the proper progesterone sensitivity regulation that is essential for successful embryo implantation.…”

The human clinical phenotypes of altered CHRNA7 copy number

“…It has been reported in a total of 11 cases in the literature [9,18,20,28,52,54–56]. Three (27.3%) of the 11 published cases are compound heterozygotes [9,56], one with BP4-BP5 and BP3-BP5 deletions, and two BP4-BP5 and D-CHRNA7-LCR-BP5 deletions.…”

“…It has been reported in a total of 11 cases in the literature [9,18,20,28,52,54–56]. Three (27.3%) of the 11 published cases are compound heterozygotes [9,56], one with BP4-BP5 and BP3-BP5 deletions, and two BP4-BP5 and D-CHRNA7-LCR-BP5 deletions. Of the other eight (72.7%%) patients, two are homozygous for D-CHRNA7-LCR-BP5 deletions [52,54], and six are homozygous for BP4-BP5 deletions [18,20,28,55] (Figures 2 & 3).…”