Interstitial microdeletion of the 1p34.3p34.2 region

Abstract

BackgroundInterstitial microdeletions of chromosome 1p34.3p34.2 are rare, but are continuing to be identified by the use of chromosome microarray. There have been fewer than 10 individuals identified who have deletions of the 1p34.3p34.2 region; all of these previously described individuals have deletions of the AGO1, AGO3, GRIK3, SLC2A1, or RIMS3 genes. Haploinsufficiency of these genes has been associated with neurodevelopmental delays.MethodsChromosome microarray, quantitative PCR, and fluorescence in situ hybridization were performed with DNA extracted from peripheral blood.ResultsChromosome microarray identified a 2.3 Mb 1p34.3p34.2 one copy deletion in our patient with global developmental delay, mild intellectual disability, delayed bone age, bilateral vesicoureteral reflux, vocal cord paralysis, right aberrant subclavian artery, kyphoscoliosis, bilateral metatarsus adductus, and valgus knee deformity. This deletion was confirmed by quantitative PCR and does not include the AGO1, AGO3, GRIK3, SLC2A1, or RIMS3 genes. Subsequent FISH testing of the parents was negative.ConclusionHaploinsufficiency of the 1p34.3p34.2 region, including the SNIP1 gene and excluding the five genes listed above, is responsible for the neurocognitive delays and other symptoms as identified in our patient.

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

“…Large deletions at the 1p34.3 locus including AGO1 together with AGO3 (and sometimes AGO4 ) among other genes were previously reported in five children with psychomotor developmental delay as well as additional non-specific features (feeding difficulty, language impairment, facial dysmorphy) 13 14. In addition, AGO2 was very recently implicated in NDD15: 21 individuals with heterozygous de novo variants in AGO2 were reported, including 11 missense variants, one in-frame deletion and one 235 kb deletion involving the first three exons of AGO2 .…”

De novocoding variants in theAGO1gene cause a neurodevelopmental disorder with intellectual disability

“…Large deletions of 1.1 Mb to 3.1 Mb at the 1p34.3 loci including AGO1 together with AGO3 (and sometimes AGO4 among other genes) were previously reported in children with NDD 13,14 . These five individuals presented with psychomotor developmental delay as well as additional non-specific features (feeding difficulty, language impairment, facial dysmorphy).…”

“…together with AGO3 (and sometimes AGO4 among other genes), and a deletion encompassing the AGO2 fist 3 exons challenges this observation [13][14][15] . AGO2 variant functional analysis revealed a complex cellular deregulation: a decrease in mRNA silencing was observed as expected for a LoF mechanism but with a variable impact, depending on the mRNA target and the tested AGO2 variant.…”

A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder

“…While the pathomolecular outcomes associated with the SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) substitution remain unclear, SNIP1 null mouse models display embryonic lethality indicating that this Amish variant may be unlikely to result in complete loss of function [ 14 ]. While no other biallelic variants in SNIP1 have conclusively been associated with genetic disease to date, Jacher and Innis (2018) reported a 17-year-old female with a de novo 2.3 Mb interstitial deletion at 1q34.3q34.2 that encompassed 43 genes, of which only two ( SNIP1 and RSPO1 ) were potentially linked with genetic disease genes at the time of publication [ 15 ]. This female had global developmental delay, mild intellectual disability, congenital defects, vocal cord paralysis, delayed bone age, and skeletal deformities.…”