Adult neuropsychiatric expression and familial segregation of 2q13 duplications

Abstract

New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.

Keywords: GABA; RHOA; SLC1A1; chromosome 16p13.11; chromosome 2q13; copy number variation; genetic counseling; genomic disorder; microRNA; obsessive-compulsive; schizophrenia.

FIG. 1

Familial segregation and genic content of 2q13 duplications and other rare CNVs. Solid and open colored bars represent gains (duplications) and losses (deletions), respectively. Start and stop coordinates for the four CNVs of interest were: chr2:111,105,101–112,832,463, chr3:49,382,869–49,443,186, chr9:4,527,834–5,014,492, and chr16:15,016,089–16,260,667. Genomic parameters are from NCBI Build 36 (hg18). All CNVs pictured were confirmed using a second method (see text). Notably, these 2q13 duplications are distal to another 2q13 locus for recurrent CNVs overlapping NPHP1 [Cooper et al., 2011]. Subject II-3 is a presumed carrier of the 9p24 deletion, given its presence in two of his offspring (III-2, III-3) and absence in their mother (II-4) and other maternal relatives. Psychiatric conditions in individuals with 2q13 duplications are outlined in Table I. In Family A, the psychiatric conditions in individuals without confirmed 2q13 duplications included: a history of untreated psychotic and paranoid features for subject I-1, lifelong “nerve problems” requiring treatment and psychotic features for subject I-2, trichotillomania and major depression for subject II-1, alcohol abuse with impulsive and violent behavior for subject II-3, and chronic paranoid schizophrenia (age at onset 28 years) and dyslexia with average IQ for subject II-5. Subject III-4 has no chronic psychiatric conditions, but has had two brief episodes of substance-induced psychosis. Of note, a distant maternal cousin (second cousin once removed) with schizophrenia (not pictured), a 6th degree relative to the proband in Family A, had neither the 2q13 duplication nor the 16p13.11 duplication, but did have a rare 1.4 Mb exonic loss overlapping five genes including LIN7A (Case 44 in [Costain et al., 2013]) that was not found in any of the individuals portrayed in this figure.