Homozygous loss of CHRNA7 on chromosome 15q13.3 causes severe encephalopathy with seizures and hypotonia

Clinical utility gene card for: 15q13.3 microdeletion syndrome

“…11 Recently, eight severely affected patients harbouring a homozygous BP4-BP5 microdeletion (n ¼ 5) or a homozygous B500 kb microdeletion of CHRNA7 (n ¼ 3) have also been described. [29][30][31][32] Interestingly, although the clinical phenotypes observed in the homozygous carriers are more severe but overall consistent with those of the patients harbouring the heterozygous microdeletions, all the five patients with homozygous BP4-BP5 microdeletions identified so far also present with a severe visual impairment phenotype, characterized by optic nerve atrophy or retinal dystrophy, never observed in individuals with 15q13.3 heterozygous microdeletions. 11,[29][30][31] The TRPM1 gene represents the most interesting candidate at 15q13.3 for the severe visual abnormalities observed in the homozygous BP4-BP5 microdeletion carriers.…”

“…[29][30][31][32] Interestingly, although the clinical phenotypes observed in the homozygous carriers are more severe but overall consistent with those of the patients harbouring the heterozygous microdeletions, all the five patients with homozygous BP4-BP5 microdeletions identified so far also present with a severe visual impairment phenotype, characterized by optic nerve atrophy or retinal dystrophy, never observed in individuals with 15q13.3 heterozygous microdeletions. 11,[29][30][31] The TRPM1 gene represents the most interesting candidate at 15q13.3 for the severe visual abnormalities observed in the homozygous BP4-BP5 microdeletion carriers. It encodes the transient receptor potential cation channel M1, a calcium permeable cation channel that mediates synaptic transmission from photoreceptors to ON bipolar cells, promoting a change in the membrane potential that results in the light-evoked response of the ON bipolar cells.…”

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

“…[1][2][3][4][5][6][7] To date, all individuals with the homozygous 15q13.3 deletion are reported to have a similar and much more severe developmental encephalopathy and neuromuscular disorder than those with the heterozygous deletion. [13][14][15][16][17] We hypothesized that the 15q13.3 deletion had detectable effects on downstream gene expression and the effects of downstream gene dysfunction might contribute to the syndrome.…”

“…Six patients with homozygous deletions of 15q13.3 have been reported [13][14][15][16][17] with a strikingly similar developmental encephalopathy that includes severe hypotonia, intractable epilepsy, and visual impairment. Although the CHRNA7 deletion is posited to cause seizures and neuropsychiatric disturbances, homozygous TRPM1 (transient receptor potential cation channel, subfamily M, member 1) deletion appears to cause visual impairment, in particular congenital stationary night blindness (CSNB).…”

Nicotinic acetylcholine receptors in human genetic disease

“…23 This is only questioned by a few reports of individuals with rare homozygous or compound heterozygous deletions involving CHRNA7, for whom parents heterozygous for the deletion are reported as healthy with normal intelligence and no history of psychiatric disorder. 24 One might conclude that the penetrance for neuropsychiatric phenotypes in individuals with deletion of CHRNA7 is high, but not quite 100%. Homozygous or compound heterozygous deletions of CHRNA7 cause a phenotype of neonatal encephalopathy, with severe hypotonia, cortical visual impairment, profound developmental and intellectual impairment, and intractable epilepsy.…”