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Expanding the phenotype of TAB2 variants and literature review.

ABSTRACT: TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome sequencing. Eight individuals had de novo variants, the other six individuals were found to have maternally inherited, or likely maternally inherited, variants. Five individuals from the same family were identified following cardiac disease gene panel in the proband and subsequent targeted familial gene sequencing. The clinical features of this cohort were compared to the existing literature. Common clinical features include distinctive facial features, growth abnormalities, joint hypermobility, hypotonia, and developmental delay. Newly identified features included feeding difficulties, sleep problems, visual problems, genitourinary abnormality, and other anatomical variations. Here we report 14 new individuals, including novel TAB2 variants, in order to expand the emerging syndromic clinical phenotype and provide further genotype-phenotype correlation.

SUBMITTER: Woods E

PROVIDER: S-EPMC9804770 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Expanding the phenotype of TAB2 variants and literature review.

Woods Emily E Marson Imogen I Coci Emanuele E Spiller Michael M Kumar Ajith A Brady Angela A Homfray Tessa T Fisher Richard R Turnpenny Peter P Rankin Julia J Kanani Farah F Platzer Konrad K Ververi Athina A Emmanouilidou Eleftheria E Bourboun Nourxan N Giannakoulas George G Balasubramanian Meena M

American journal of medical genetics. Part A 20220816 11

TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome seque ...[more]

PMID: 35971781

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Project description:BackgroundShashi-Pena syndrome (SHAPNS) is a developmental disorder caused by mutations in additional sex combs-like Protein 2 (ASXL2). Since 2016, only 12 cases from 10 families have been reported. However, neonatal period characteristics remain largely unknown. Herein, we report a case with a pathogenic variant in ASXL2 in a newborn.Case descriptionA newborn was diagnosed with a previously unreported de novo truncating mutation in ASXL2 (NM_018263.6) at 21 days and the clinical characteristics of all probands with ASXL2-related SHAPNS was reported in the literature. He had persistent hypoglycemia caused by inappropriate insulin levels and achieved stable glucose levels after octreotide treatment. Magnetic resonance imaging (MRI) revealed a small cerebellum, and fundoscopy showed bilateral retinal paving-stone-like white lesions. The results of trio-based whole exome sequencing (WES) were returned on the 21st day of life, and a heterozygous de novo truncating pathogenic c.1792C>T (p.Gln598*) variant in exon 11 of the ASXL2 gene was identified. The clinical features of our patient and another 10 probands with ASXL2-related SHAPNS reported in the literature were included in this review. More than half shared recognizable clinical features, including hypertelorism (11/11), broad nasal tip (10/11), arched eyebrows (9/11), a large V-shaped glabellar nevus flammeus on the forehead (9/11), low-set ears (8/11), posteriorly rotated ears (7/11), proptosis (6/11) and deep palm creases (6/11). Major clinical issues included feeding difficulties (10/11), developmental delay (10/11), skeletal and/or extremity abnormalities (8/11), progressive macrocephaly (8/11), hypotonia (8/11), hypoglycemia (6/11) and seizures (6/11). Neurodevelopmental regression was possible in patients (2/11) with normal MRI findings who later developed nonfebrile seizures.ConclusionsWe present a newborn diagnosing the SHAPNS by trio-WES, which is the earliest age of diagnosis. The application of octreotide for hypoglycemia, the small cerebellum and bilateral paving-stone-like white lesions of the retinas are described for the first time in an individual with ASXL2-related SHAPNS. Additional clinical reports of neonates with damaging ASXL2 variants are necessary to verify the mechanism and optimal treatment of ASXL2-related hypoglycemia, neurological damage and optic impairment. Neurological, endocrinological, ophthalmological, and rehabilitative follow-ups of these patients are necessary and important.

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Expanding the phenotype of TAB2 variants and literature review.

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Expanding the phenotype of TAB2 variants and literature review.

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