Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay

Burnside, Rachel D.; Pasion, Romela; Mikhail, Fady M.; Carroll, Andrew J.; Robin, Nathaniel H.; Youngs, Erin L.; Gadi, Inder K.; Keitges, Elizabeth; Jaswaney, Vikram; Papenhausen, Peter; Potluri, Venkateswara R.; Risheg, Hiba; Rush, Brooke; Smith, Janice; Schwartz, Stuart; Tepperberg, James; Butler, Merlin G.

doi:10.1007/s00439-011-0970-4

Cited by 226 publications

(221 citation statements)

References 47 publications

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“…The 15q11.2(BP1-BP2) deletion has previously been shown to confer modest risk of schizophrenia 1 , behavioural disturbances 17 , developmental and language delay 18 , and epilepsy 19 . We show that the 15q11.2(BP1-BP2) deletion has only modest impact on results of the neuropsychological tests but is still strongly associated with a history of difficulties in learning mathematics and reading (Fig.…”

Section: Lm I Andmentioning

confidence: 99%

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Stefánsson

Meyer‐Lindenberg

Steinberg

et al. 2013

Nature

626

568

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In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNVonly confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.Little information is available on whether or how rare CNVs conferring high risk of schizophrenia and/or autism affect physiologic function of otherwise normal brains. As none of these CNVs hitherto described are fully penetrant for the diseases, and both schizophrenia and autism affect cognition, we aimed to examine the possibility that the CNVs affect cognition in control carriers, those who do not suffer either disease or intellectual disability. We based our selection of CNVs on a literature search for CNVs associated with schizophrenia and/or autism ('neuropsychiatric CNVs'); this search produced 26 CNV alleles (Supplementary Table 1) 1-3 . These CNV alleles are rare, found in 0.002% to 0.2% frequency, and cumulatively in 1.16% of our sample of 101,655 genotyped subjects, representing approximately one-third of the Icelandic population ( Supplementary Tables 1 and 2).We used the subset of genotyped subjects born before 1968, without excluding patients, to examine the association of each neuropsychiatric CNV with reproductive outcome ('fecundity'), defined simply as the number of children each subject had by age 45. After correction for multiple comparisons, three neuropsychiatric CNVs were significantly associated with fecundity (Table 1). Subjects carrying the 16p11.2 deletion or the 22q11.21 duplication show reduced fecundity, with the effect in males significantly greater than in females (P 5 0.0083 and P 5 0.029 for the difference in effect by sex for the 16p11.2 deletion and the 22q11.21 duplication, respectively). In contrast, individuals carrying the 16p12.1 deletion have more children than do controls (Table 1). Those with deletions at 15q11.2(...

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Section: Lm I Andmentioning

confidence: 99%

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Stefánsson

Meyer‐Lindenberg

Steinberg

et al. 2013

Nature

626

568

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“…Such family analysis highlights the difficulty of predicting the recurrence risk of del15q11.2. Second alterations were also found in 25% (17/69) of del15q11.2 patients by Burnside et al In one of the patients the second CNV was confirmed de novo [Burnside et al, 2011]. In the study of Girirajan et al [2012] the del15q11.2 was the most likely genomic disorder where additional large variants occurred in affected children in comparison to controls (P ¼ 0.00093).…”

Section: Clinical Reports and Association Studiesmentioning

confidence: 79%

“…Only 32% of patients presented with ASD and 29% of patients with ID. In the series of Burnside et al the most common feature in del15q11.2 patients was delayed speech [Burnside et al, 2011].…”

Section: Clinical Reports and Association Studiesmentioning

confidence: 95%

“…2) [Stefansson et al, 2008;Kirov et al, 2009;Mefford et al, 2009;de Kovel et al, 2010;Burnside et al, 2011;Cooper et al, 2011;Kommu et al, 2011;Leblond et al, 2012;Rosenfeld et al, 2012]. In addition, a combined study of phenotypes in del15q11.2 patients showed that 67% of patients had behavioral/ neurological problems and 64% had general developmental delay.…”

Section: Clinical Reports and Association Studiesmentioning

confidence: 99%

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Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example

Wolf

Brison

Devriendt

et al. 2013

American J of Med Genetics Pt A

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In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented.

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“…Maternally inherited 15q11-13 duplication is a well described cause of neurodevelopmental phenotypes similar to those in our family, including developmental, speech and motor delays, autism or ASD, seizures, ADD/ADHD, ODD, self-injury and tantrums. 4,9 Only one case of an individual with a neurodevelopmental disorder involving the GABA A cluster on 6q15 (GABRR1 and GABRR) has been reported. 10 This 22-year-old female had intellectual disability, ataxia and severe speech deficiency, with an inversion and a deletion described as 46,XX, del(6)(q13q15),inv(6)(p11.2q15 46,XX, del(6)(q13q15),inv(6)(p11.2q15).…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

et al. 2013

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Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABA A ). Clusters of GABA A receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABA A receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABA A receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.

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Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay

Cited by 226 publications

References 47 publications

CNVs conferring risk of autism or schizophrenia affect cognition in controls

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

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