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A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

ABSTRACT: Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia. Craniofacial dysmorphism consisted of a triangular face with a prominent forehead and midface hypoplasia. Magnetic resonance imaging (MRI) demonstrated thinning of the corpus callosum and paucity of white matter. Genome-wide linkage analysis identified a single ~4 Mbp disease-associated locus on chromosome 7q21.13-q21.3 (LOD score>5). Whole-exome and genome sequencing identified no nonsynonymous pathogenic biallelic variants in any of the genes within this locus. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.

SUBMITTER: Halperin D

PROVIDER: S-EPMC9545274 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

Halperin Daniel D Agam Nadav N Hallak Maher M Feinstein Miora M Drabkin Max M Yogev Yuval Y Wormser Ohad O Shavit Eitan E Gradstein Libe L Shelef Ilan I Mijalovsky Aanalia A Flusser Hagit H Birk Ohad S OS

Clinical genetics 20220505 2

Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, a ...[more]

PMID: 35443069

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Project description:Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

Dataset Information

A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

Publications

A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

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