A novel maternally inherited 8q24.3 and a rare paternally inherited 14q23.3 CNVs in a family with neurodevelopmental disorders

Abstract

A 7-year-old female with developmental delay (DD), autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), and seizures was referred to our laboratory for oligomicroarray analysis. The analysis revealed a 540 kb microdeletion in the chromosome 8q24.3 region (143,610,058-144,150,241) encompassing multiple genes. Two siblings of the proband were also analyzed. The proband's older sister with DD, seizures, and ASD has a 438 kb intragenic microdeletion of the GPHN gene in the chromosome 14q23.3 region (67,105,512-67,543,291) containing multiple exons, while the proband's older brother with DD, ASD, ID, and ADHD has both the 8q24.3 and the 14q23.3 deletions. All three siblings have a normal karyotype at the 650 G-band level of resolution. Parental FISH analysis indicates that the mother is a carrier for the 8q24.3 deletion and the father is a carrier for the 14q23.3 deletion. The 8q24.3 deletion seen in our patients has not been reported in the literature, while the small deletions of the 14q23.3 region involving multiple exons of the GPHN gene have been reported in a handful of patients in a recent study. The size of the 8q24.3 deletion and its genomic content, as well as the maternal family history, strongly suggest the association between the deletion and the neurodevelopmental disorders. Our study also provides more evidence in support of the association between GPHN deletion and neurodevelopmental disorders.

Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

“…Arc chromosomal micro-deletion and intragenic SNP have also been found in association with neurodevelopmental disorders such as schizophrenia (Hu et al, 2015, Huentelman et al, 2015). In addition, reduced expression of Arc mRNA has been detected in the PFC of individuals with schizophrenia (Guillozet-Bongaarts et al, 2014).…”

The FRA14B common fragile site maps to a region prone to somatic and germline rearrangements within the large GPHN gene

“…Loss‐in‐size variants are shown in red, and gain‐in‐size variants in blue. C, Rare exonic deletions in patients with neurodevelopmental disorders reported by Lionel et al, Dejanovic et al, and Hu et al ASD, autistic spectrum disorders; DD, developmental delay; IGE, idiopathic generalized epilepsy. FRA14B is highlighted in a light shade of gray; the dark gray bar indicates the core region of fragility…”

A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate

“…However, in our samples of acrophobia with comorbid schizophrenia (LOD = 0.51) and pure schizophrenia (LOD = 0.00) this region did not provide evidence for linkage. This region encompasses 49 genes, including several candidate genes for psychiatric disorders: potassium voltage-gated channel subfamily KQT member 3 ( KCNQ3 )2428 coding for a voltage-gated potassium channel; adenylate cyclase 8 ( ADCY8 )24 involved in fear learning and memory, and long-term memory consolidation29; Ly6/Neurotoxin 1 ( LYNX1 )30 (located on 8q24.3 near D8S373) involved in the development of visual perception including binocular vision and motor learning during the critical period31323334; and activity-regulated cytoskeleton-associated protein ( ARC )29 connected to long-term potentiation and the consolidation of long-term memory. Our strongest evidence for LD conditional on linkage (P = 0.0054, dominant model) was observed with markers located in chromosomal region 17p11.…”