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Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

ABSTRACT: BACKGROUND:KBG syndrome, a rare autosomal disorder characterised by distinctive craniofacial and skeletal features and developmental delay, is caused by haploinsufficiency of the ANKRD11 gene. RESULTS:Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype. In the siblings, array-based comparative genomic hybridization (array CGH) identified an intragenic microduplication affecting ANKRD11 that was absent from the parents' array CGH profiles. Microsatellite analysis revealed the maternal origin of the rearrangement and interphase fluorescent in situ hybridization (i-FISH) experiments identified the rearrangement in low-level mosaicism in the mother. Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein. CONCLUSIONS:Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome.

SUBMITTER: Crippa M

PROVIDER: S-EPMC4383199 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

Crippa Milena M Rusconi Daniela D Castronovo Chiara C Bestetti Ilaria I Russo Silvia S Cereda Anna A Selicorni Angelo A Larizza Lidia L Finelli Palma P

Molecular cytogenetics 20150326

<h4>Background</h4>KBG syndrome, a rare autosomal disorder characterised by distinctive craniofacial and skeletal features and developmental delay, is caused by haploinsufficiency of the ANKRD11 gene.<h4>Results</h4>Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype. In the siblings, array-based comparative genomic hybridization (array CGH) identified an intragenic microduplication affecting ANKRD11 that was absent from the parents ...[more]

PMID: 25838844

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Project description:BackgroundKBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome.Case presentationA 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole-exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident.ConclusionsThe results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.

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Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

Publications

Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

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