Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications

Rosenfeld, Jill A.; Coppinger, Justine; Bejjani, Bassem A.; Girirajan, Santhosh; Eichler, Evan E.; Shaffer, Lisa G.; Ballif, Blake C.

doi:10.1007/s11689-009-9037-4

Cited by 165 publications

(177 citation statements)

References 22 publications

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“…Premature balding, present in the previously reported family, was not present in our cohort, which may be due to the relative younger ages of the subjects. Similar to other genomic disorders that have heterogeneous clinical phenotypes, [34][35][36] our cohort displays phenotypic variability. In addition, there have been healthy carriers of this microduplication in the family reported by Grisart et al 22 and in a father in our cohort.…”

Section: Discussionmentioning

confidence: 57%

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: Discussionmentioning

confidence: 57%

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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“…For some human CNV-associated syndromes such as 7q11.23 deletion (i.e., Williams-Beuren syndrome) and the reciprocal duplication (42), loss and gain are associated with opposing clinical features. Indeed, this is the case for head size alterations associated with 16p11.2 CNVs (16), but certainly not for behavioral symptoms of these patients (10,13,16). In mice, we see that loss and gain of 16p11.2 cause distinct and opposing behavioral phenotypes.…”

Section: Resultsmentioning

confidence: 82%

“…Several human studies compared the behavioral symptoms of patients with 16p11.2 deletions and duplications (10,13,16); however, to our knowledge, there is no evidence that loss and gain of 16p11.2 affect behavior in opposing ways. Even with patients harboring the same 16p11.2 lesion, there is a broad spectrum of clinical symptoms, some patients being severely affected and others highly functional.…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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“…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: 94%

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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Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications

Cited by 165 publications

References 22 publications

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

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

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

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

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