3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

Abstract

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features--including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation--were observed, but each feature was only found once, in a single patient. The microdeletion is approximately 1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…The 3q29 microdeletion syndrome has been recently described as a new syndrome, probably caused by nonallelic homologous recombination. 31 It was usually associated with dysmorphism, mild-to-moderate ID, variable congenital malformations and ASD in 27% of cases. 32 This CNV was also recently found in schizophrenic individuals.…”

The genetic variability and commonality of neurodevelopmental disease

“…Presented is a model where an increasing number of genes disrupted by rare CNVs correlates with an increase in phenotypic severity (defined as increasing comorbidity of ID and congenital abnormalities). a All loci (except 3q29) [Girirajan et al, unpublished], 7q11.23 deletion [Perez Jurado et al, 1996], 3q29 deletion [Willatt et al, 2005;Ballif et al, 2008], and 17q21.31 [Koolen et al, 2008]. b 17q21.21 does not demonstrate variable expressivity.…”

“…The 3q29 microdeletion is particularly rare (<1/1,000) and has been associated with severe schizophrenia , ID, and autistic features with mild dysmorphism present in the majority of cases [Willatt et al, 2005;Ballif et al, 2008]. Recently, Carroll et al, [2011] identified rare mutations in one gene (DLG1) highlighting its potential involvement in the schizophrenia phenotype.…”

Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia

“…This analysis was further facilitated by the inclusion of mapping data derived from a reported 3q microdeletion syndrome, characterized by skeletal abnormalities and mental retardation but not by hematopoietic deficiencies, and, of note, not deleting RPL35A ( Figure 2). 24 Based on their roles in erythropoiesis, 2 genes in the initial deletion region considered as potential candidates, TFRC, the transferrin receptor 1, and HES1, a Notch1 signaling protein that regulates erythropoiesis via interaction with GATA1, were considered unlikely gene candidates because they were not included in both deletions (HES1), failed to show a difference in expression level in deletion 1 LCL by microarray (HES1), or fell within the region of the 3q microdeletion syndrome (TFRC).…”