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CHRNA7 Triplication Associated with Cognitive Impairment and Neuropsychiatric Phenotypes in a Three-Generation Pedigree

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CHRNA7 Triplication Associated with Cognitive Impairment and Neuropsychiatric Phenotypes in a Three-Generation Pedigree European Journal of Human Genetics (2014) 22, 1071–1076 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree Claudia Soler-Alfonso1, Claudia MB Carvalho2,3, Jun Ge2, Erin K Roney2, Patricia I Bader4, Katarzyna E Kolodziejska2, Rachel M Miller4, James R Lupski2,5, Pawel Stankiewicz2, Sau Wai Cheung2, Weimin Bi2 and Christian P Schaaf*,2,6 Although deletions of CHRNA7 have been associated with intellectual disability (ID), seizures and neuropsychiatric phenotypes, the pathogenicity of CHRNA7 duplications has been uncertain. We present the first report of CHRNA7 triplication. Three generations of a family affected with various neuropsychiatric phenotypes, including anxiety, bipolar disorder, developmental delay and ID, were studied with array comparative genomic hybridization (aCGH). High-resolution aCGH revealed a 650-kb triplication at chromosome 15q13.3 encompassing the CHRNA7 gene, which encodes the alpha7 subunit of the neuronal nicotinic acetylcholine receptor. A small duplication precedes the triplication at the proximal breakpoint junction, and analysis of the breakpoint indicates that the triplicated segment is in an inverted orientation with respect to the duplication. CHRNA7 triplication appears to occur by a replication-based mechanism that produces inverted triplications embedded within duplications. Co-segregation of the CHRNA7 triplication with neuropsychiatric and cognitive phenotypes provides further evidence for dosage sensitivity of CHRNA7. European Journal of Human Genetics (2014) 22, 1071–1076; doi:10.1038/ejhg.2013.302; published online 15 January 2014 Keywords: dosage sensitivity; copy number variation; cholinergic nervous system; autism spectrum disorder INTRODUCTION 1in180,6 have been more challenging to interpret, as they do not Copy number variants (CNVs) of chromosome 15q13.3 have been manifest the high penetrance of neuropsychiatric phenotypes seen in associated with multiple neurological and neuropsychiatric pheno- deletion cases. Van Bon et al2 first reported four patients with types.1 In general, there are two different sizes of recurrent nonallelic cognitive impairment and psychiatric disorders coinciding with BP4 homologous recombination (NAHR)-mediated deletions and and BP5 duplications. This was followed by the description of 55 duplications at this locus: the larger CNVs utilize BP4 and BP5 as cases of smaller-sized CHRNA7 duplications (350–680 kb in size).7 substrate pairs, and typically involve a 1.6-Mb genomic interval, The latter report provided clinical data and pedigree analysis of 11 whereas the smaller CNVs arise between two CHRNA7-low copy families and suggested that the duplication may be associated with repeat (LCR) copies, and are 350–680 kb in size. Although the larger DD, ID, and a variety of neuropsychiatric phenotypes, but with high deletion and duplication harbor six RefSeq genes (MTMR15, variability in expressivity and reduced penetrance. Additional studies MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7)andonemiRNA showed that 15q13.3 duplications were not associated with (hsa-mir211), the smaller deletion and duplication CNV encompass schizophrenia,5 but significantly associated with DD and ID.4 only the entire CHRNA7 gene and the first exon of a non-coding Furthermore, the small CHRNA7 duplication was found as a risk RNA-variant of OTUD7A. The BP4 and BP5 microdeletion has been factor for attention deficit hyperactivity disorder.8 found in patients with developmental delay/intellectual disability Here, we report triplication of CHRNA7, segregating in four (DD/ID), epilepsy, autism, schizophrenia and other neurocognitive affected family members in three generations (Figure 1). We present disorders.1,2 CHRNA7 was considered the likely culprit gene to cause a detailed clinical and behavioral characterization of the affected neurological phenotypes in patients with the 15q13.3 deletion, which individuals. was subsequently confirmed by the identification of the small (680 kb) CHRNA7 deletion, manifesting a similar phenotypic spectrum as the Clinical description larger deletion.3 Follow-up studies have strongly associated 15q13.3 The propositus (III-2) was a 10-year-old boy at the time he presented deletions with both DD/ID4 and schizophrenia.5 to the genetics clinic for evaluation of ID and autistic behaviors. The reciprocal microduplications of 15q13.3, which are very The boy was born as a monozygotic twin conceived naturally by common in the general population with an estimated frequency of a 26-year-old mother and 30-year-old father. Both parents were 1Department of Pediatrics, Division of Medical Genetics, University of Texas Health Science Center, Houston, TX, USA; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 3Centro de Pesquisas Rene´ Rachou – FIOCRUZ, Belo Horizonte, Brazil; 4Parkview Health Laboratories, Genetics Center, Fort Wayne, IN, USA; 5Department of Pediatrics, Texas Children’s Hospital, Houston, TX, USA; 6The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA *Correspondence: Dr CP Schaaf, The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, 1250 Moursund Street, Suite 1350, Houston, TX 77030, USA. Tel: +1 832 824 8787; Fax: +1 832 825 1251; E-mail: [email protected] Received 26 July 2013; revised 30 October 2013; accepted 27 November 2013; published online 15 January 2014 CHRNA7 triplication and neuropsychiatric phenotypes C Soler-Alfonso et al 1072 evaluation, he was 10 years old and was able to follow one-, but not two-step commands. He was enrolled in special education classes. A short attention span, impulsive behavior and aggressiveness to his classmates had been reported. Like his brother, he did not tolerate changes in his routine. A formal neuropsychological evaluation revealed dysthymia, anxiety disorder, PDD-NOS, language processing deficits, and borderline intellectual functioning (full scale IQ of 84 on the Wechsler Intelligence Scale for Children IV), with significantly more salient non-verbal than verbal functions, impaired language functions, impaired memory functions and impaired cognitive flexibility. On physical examination, he manifested mild dysmorphic features similar to his twin brother (Figure 1, III-3), had mild dysarthria, some coordination difficulties, and generalized hypotonia. At 2 years of age, a head CT had been obtained after accidental head trauma, revealing a left middle cranial fossa arachnoid cyst, which was later confirmed by MRI at 10 years. Routine genetic evaluation and diagnostic testing for both twin brothers included chromosome analysis, FISH analysis for Sotos syndrome, PTEN sequencing, and Fragile X testing. The twins’ mother (II-3) was 37 years old at the time of examination. She had a history of DD and did not walk until 2–3 years of age. Her medical history was significant for bipolar disorder, Figure 1 Three generation family with CHRNA7 triplication. Trip, CHRNA7 anxiety disorder, attention deficit disorder, learning disability, and triplication; wt, wildtype (tested for CHRNA7 copy number by FISH, with seizures since her twenties. At the time of examination, she lived in an normal result). Patient photographs: individuals III-2 and III-3 at 10 years assisted living facility. Her physical examination was remarkable for of age, individual II-3 at 37 years of age. bilateral prominent antihelices, bulbous nasal tip, mildly flat philtrum and a fine resting tremor (Figure 1, II-3). The twins’ half siblings of Caucasian descent. The twins were born by spontaneous vaginal (III-1 and III-4) were reported as healthy with normal physical delivery at approximately 36 weeks of gestation. The proband’s birth appearance, and normal development. Both attended regular schools weight was 1.955 kg (10th–25th percentile). The birth head circum- with no learning difficulties. Individuals II-2 (the twins’ father) and ference and length were not available for review. He was hospitalized I-2 (maternal grandmother) were in good physical health, with no in the neonatal intensive care unit for 1 week because of mild feeding cognitive impairment and no history of neuropsychiatric disease. difficulties. Infancy and early childhood were significant for speech Clinical information on the twins’ maternal grandfather (I-1) is very delay, with active intervention speech therapy started at 2 years of age, limited, but significant for alcoholism, drug addiction, and abusive and cognitive impairment. Motor development was reported as behaviors to family members. Reportedly, he had multiple family normal. At the time of examination, he was in the fourth grade, members with a history of alcoholism. enrolled in general and special education classes. He was able to follow two-step commands, but required constant repetition and redirection. A short attention span had been noted, as well as low METHODS frustration tolerance. He had transition difficulties and did not The index case was referred to the Medical Genetics Laboratories at Baylor tolerate changes in his routine. His emotional profile was significant College of Medicine (BCM), Houston, TX, USA, for clinical array comparative for anxiety and depression. A formal developmental and neuropsy- genomic hybridization (aCGH) analysis. DNA was extracted from whole blood chological assessment was performed at 10 years and 7 months of age using the
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