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22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

ABSTRACT: Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

SUBMITTER: Ujfalusi A

PROVIDER: S-EPMC7445545 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

Ujfalusi Anikó A Nagy Orsolya O Bessenyei Beáta B Lente Györgyi G Kántor Irén I Borbély Ádám J ÁJ Szakszon Katalin K

Molecular syndromology 20200404 3

Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low- ...[more]

PMID: 32903739

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Project description:BackgroundCommon clinical findings in patients with 19p13.3 duplication include intrauterine growth restriction, intellectual disability, developmental delay, microcephaly, and distinctive facial features. In this study, we report the case of a patient with 19p13.3 microduplication and novel clinical findings, specifically nephrotic syndrome.Case presentationsA 4-year-old girl was admitted to our hospital in December 2020 with a fever and cough that had persisted for 3 days. A series of treatments, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were performed. Relevant literature was reviewed using the search terms "19p13.3" and "19p13.3 microduplication syndrome" in the China Knowledge Network, Wanfang Database, Weipu Journal Service Platform, and PubMed (date range: database establishment to September 2023). In addition to common symptoms, such as developmental delay, microcephaly, distinctive facial features, and congenital heart defects, the patient also had nephrotic syndrome, a previously unreported phenomenon. CMA results showed a 3.6 Mb fragment duplication (copy number: 3) in the chr19p13.3 region, containing 127 protein-coding genes (including CELF5, NFIC, SMIM24, PIAS4, ATCAY, MAP2K2, and ZBTB7A). WES revealed a filamin C mutation (p.Glu309Valfs × 11). The mutation status of the patient and her father was heterozygous, whereas the mutation was not detected in the mother.ConclusionMicroduplication in the 19p13.3 region could be one of the genetic factors contributing to the observed clinical phenotypes. However, patients with developmental delay, microcephaly, distinctive facial features, congenital heart defects, and urogenital system disorders may exhibit these manifestations due to various genetic syndromes; therefore, simply considering the possibility of 19p13.3 microduplication syndrome based on these non-specific features is not sufficient. Further comprehensive evaluations, including CMA, should be conducted in conjunction with other genetic tests and detailed clinical examinations to accurately determine the underlying genetic causes.

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Project description:Background22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.MethodsA serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.ResultsThirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.ConclusionsThis study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

Dataset Information

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

Publications

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

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