Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader–Willi critical region, possibly associated with behavioural disturbances

Doornbos, M.; Sikkema‐Raddatz, Birgit; Ruijvenkamp, Claudia A. L.; Dijkhuizen, Trijnie; Bijlsma, Emilia K.; Gijsbers, Antoinet C.J.; Hilhorst‐Hofstee, Yvonne; Hordijk, Roel; Verbruggen, Krijn T.; Kerstjens-Frederikse, Wilhelmina S.; Essen, Ton van; Kok, Klaas; Silfhout, Anneke T van; Breuning, Martijn H.; Ravenswaaij-Arts, Conny M. A. van

doi:10.1016/j.ejmg.2009.03.010

Cited by 156 publications

(151 citation statements)

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“…This deletion has been implicated as a risk factor for a variety of neurocognitive disorders including behavioral problems and idiopathic generalized epilepsy. [27][28][29][30][31] It is often inherited from a normal or mildly affected parent and has also been seen in normal control individuals. 27,28,30,31 Additional clinically significant copy-number alterations were not identified in any of the remaining subjects.…”

Section: Results Molecular Analysismentioning

confidence: 99%

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

Moles

Gowans

Gedela

et al. 2012

Genetics in Medicine

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Purpose: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low-copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. methods:We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. Results:The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father.conclusion: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome.Genet Med 2012:14(5):508-514

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Section: Results Molecular Analysismentioning

confidence: 99%

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

Moles

Gowans

Gedela

et al. 2012

Genetics in Medicine

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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

612

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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“…Cyfip1 and Cyfip2 are members of a highly conserved gene family 52 , and dysregulation of Cyfip1 expression levels leads to pathological changes in neuronal maturation and connectivity, both of which may contribute to the development of the neurological symptoms observed in ASD and schizophrenia 63 . A CNV in the 15q11.2 region of the human genome has been implicated in several neurological and neuropsychiatric conditions [64][65][66][67][68][69][70] and a CYFIP1 CNV within 15q11.2 has been linked to ASD 71 , with an upregulation of CYFIP1 mRNA being demonstrated in genomewide expression profiling of ASD patients with 15q11-q13 duplication 72 . A rare CYFIP1 deletion has also been reported in a patient with a mild intellectual disability and a pervasive developmental disorder not otherwise specified 71 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%