Duplication of Chromosome 16p13.11-p12.3 with Different Expressions in the Same Family

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Abstract

The knowledge about genetic involvement in neurodevelopmental disorders, and especially in autism, is currently rising. To date, more than 100 gene mutations related to autistic syndromes have been described. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited. Recently, array comparative genomic hybridization (aCGH) has identified sub microscopic deletions and duplications as a common cause of mental retardation and autism. In this article we report the occurrence of the same genetic finding (chromosome 16p13.11-p12.3 duplication) in a family with four small children, where two older siblings manifested a global neurodevelopmental delay associated with an autism spectrum disorder (ASD), but younger twin brothers with the same mutation, have typical development. Genetic analysis showed that the chromosomal duplication was inherited from the father, in which phenotype and functioning are quite typical. As is known, the duplication can pass from parents to children. The 16p13.11 micro duplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance.

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Association between microdeletion and microduplication at 16p11.2 and autism.

Lauren A Weiss, Yiping Shen, Joshua M. Korn … (2008)

Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.

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Population analysis of large copy number variants and hotspots of human genetic disease.

Andy Itsara, Gregory M. Cooper, Carl Baker … (2009)

Copy number variants (CNVs) contribute to human genetic and phenotypic diversity. However, the distribution of larger CNVs in the general population remains largely unexplored. We identify large variants in approximately 2500 individuals by using Illumina SNP data, with an emphasis on "hotspots" prone to recurrent mutations. We find variants larger than 500 kb in 5%-10% of individuals and variants greater than 1 Mb in 1%-2%. In contrast to previous studies, we find limited evidence for stratification of CNVs in geographically distinct human populations. Importantly, our sample size permits a robust distinction between truly rare and polymorphic but low-frequency copy number variation. We find that a significant fraction of individual CNVs larger than 100 kb are rare and that both gene density and size are strongly anticorrelated with allele frequency. Thus, although large CNVs commonly exist in normal individuals, which suggests that size alone can not be used as a predictor of pathogenicity, such variation is generally deleterious. Considering these observations, we combine our data with published CNVs from more than 12,000 individuals contrasting control and neurological disease collections. This analysis identifies known disease loci and highlights additional CNVs (e.g., 3q29, 16p12, and 15q25.2) for further investigation. This study provides one of the first analyses of large, rare (0.1%-1%) CNVs in the general population, with insights relevant to future analyses of genetic disease.

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Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.

Beth A Kozel, Sarah Savage, Gary Clark … (2010)

Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.

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Author and article information

Journal

Journal ID (nlm-ta): Balkan J Med Genet

Journal ID (publisher-id): bjmg

Journal ID (pmc): bjmg

Title: Balkan Journal of Medical Genetics : BJMG

Publisher: Sciendo

ISSN (Print): 1311-0160

ISSN (Electronic): 2199-5761

Publication date Collection: June 2021

Publication date (Electronic): 27 July 2021

Volume: 24

Issue: 1

Pages: 89-94

Affiliations

[1 ]Department of Medicine, Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts , Skopje, Republic of North Macedonia

[2 ]Department of Psychophysiology, University Children’s Hospital, Faculty of Medicine, University “Cyril and Methodius,” Skopje, Republic of North Macedonia

[3 ]Department of Endocronology and Genetics, University Clinic for Children’s Diseases, Medical Faculty, University Sv. Kiril i Metodij , Skopje, Republic of North Macedonia

Author notes

[* ] Professor Nadica Pop-Jardonica, Department of Medicine, Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Bul. Krste Misirkov 2, 1000 Skopje, Republic of North Macedonia. Tel.: +389-2-32-35-400. Fax: +389-2-32-35-423. popjordanova.nadica@ 123456gmail.com

Article

Publisher ID: bjmg-2021-0010

DOI: 10.2478/bjmg-2021-0010

PMC ID: 8366479

PubMed ID: 34447664

SO-VID: fb62c3dc-756c-45e6-b89e-0440b5eada97

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This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Duplication of Chromosome 16p13.11-p12.3 with Different Expressions in the Same Family

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Most cited references 18

Association between microdeletion and microduplication at 16p11.2 and autism.

Population analysis of large copy number variants and hotspots of human genetic disease.

Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.

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