Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Bijlsma, Emilia K.; Gijsbers, Antoinet C.J.; Schuurs-Hoeijmakers, Janneke; Haeringen, Arie van; Putte, Dietje E. Fransen van de; Anderlid, Britt‐Marie; Lundin, Johanna; Lapunzina, Pablo; Jurado, L.A. Pérez; Chiaie, Barbara Delle; Loeys, Bart; Menten, Björn; Oostra, Anna; Verhelst, Hélène; Amor, David J.; Bruno, Damien L.; Essen, A.J. van; Hordijk, Roel; Sikkema‐Raddatz, Birgit; Verbruggen, Krijn T.; Jongmans, Marjolein C. J.; Pfundt, Rolph; Reeser, H.M.; Breuning, Martijn H.; Ruivenkamp, Claudia

doi:10.1016/j.ejmg.2009.03.006

Cited by 235 publications

(263 citation statements)

References 22 publications

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“…1 Another study reported 'speech retardation' (p.85) in 19 of 20 (95%) patients with 16p11.2 deletions. 8 Other studies have found speech and language deficits in 17 of 18 (94%) patients with 16p11.2 deletions, 9 and language deficits in 18 of 21 (86%) patients. 4 In a study reporting developmental milestones for speech-language acquisition in 9 patients with 16p11.2 deletions, 6 (67%) patients had significant delays in age of single word acquisition, 7 (78%) had delays in age of phrase development, and all 9 (100%) had deficits in reciprocal conversation.…”

Section: Introductionmentioning

confidence: 91%

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

et al. 2012

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We report clinical findings that extend the phenotype of the B550 kb 16p11.2 microdeletion syndrome to include a rare, severe, and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech (CAS). CAS is the speech disorder identified in a multigenerational pedigree ('KE') in which half of the members have a mutation in FOXP2 that co-segregates with CAS, oromotor apraxia, and low scores on a nonword repetition task. Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive, language, speech, oral mechanism, motor, and developmental histories and performance. Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS. Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient. These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research. We discuss implications of findings for issues in both literatures.

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Section: Introductionmentioning

confidence: 91%

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

et al. 2012

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“…In three instances, de novo CNVs were identified in a pair of nonmonozygotic siblings representing potential germline mosaicism and were counted as single events. Several de novo CNVs occur both at loci previously associated with variable phenotypes, including autism (AmosLandgraf et al 1999;McDermid and Morrow 2002;Veltman et al 2005; The International Schizophrenia Consortium 2008; Kumar et al 2008;Mefford et al 2008;Weiss et al 2008;Ben-Shachar et al 2009;Bijlsma et al 2009;Miller et al 2009), as well as sites of recurrent CNV not previously associated with autism (Kurotaki et al 2002;Bochukova et al 2010;Walters et al 2010). …”

Section: Agre Autism Analysismentioning

confidence: 99%

De novo rates and selection of large copy number variation

et al. 2010

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While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of~30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of m = 1.2 3 10 -2 CNVs per genome per transmission (m = 6.5 3 10 -3 for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 3 10 -3 ) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.

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“…Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9,10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12)(13)(14)(15)(16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16).…”

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confidence: 99%

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Horev

Ellegood²,

Lerch³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

308

342

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Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.Home-cage | stereotypic behavior | structural variation | brain MRI A ccumulating evidence suggests the importance of copy number variations (CNVs) in the etiology of neuropsychiatric disorders, including autism (1), schizophrenia (2-4), developmental delay (5), and other complex traits (6). The 16p11.2 region is particularly intriguing. Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9, 10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12-16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).Mouse models allow direct assessment of CNVs while reducing variability caused by genetic and environmental factors. We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21-24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27)). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by usin...

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Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Cited by 235 publications

References 22 publications

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

De novo rates and selection of large copy number variation

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

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