Familial segregation of a 5q15‐q21.2 deletion associated with facial dysmorphism and speech delay
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We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of CHD1 to be contributing to the clinical features observed in this family.Keywords:
Haploinsufficiency
Facial dysmorphism
Speech delay
Gene deletion
Haploinsufficiency
Microcephaly
Speech delay
Microdeletion syndrome
Angelman Syndrome
Global developmental delay
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Abstract Mutations in the MEF2C (myocyte enhancer factor 2) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the MEF2C gene, further cases with point mutations and partial gene deletions of the MEF2C gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype. We aim to add to the current knowledge of the natural history of the “MEF2C haploinsufficiency syndrome” as well as of the differential diagnosis, clinical management, and genetic counseling in this diagnostically challenging group of patients.
Haploinsufficiency
MEF2C
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The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.
Haploinsufficiency
Global developmental delay
Speech delay
Chromodomain
Comparative genomic hybridization
Macrocephaly
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We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of CHD1 to be contributing to the clinical features observed in this family.
Haploinsufficiency
Facial dysmorphism
Speech delay
Gene deletion
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Zhu-Tokita-Takenouchi-Kim syndrome is a multisystem disorder resulting from haploinsufficiency in the SON gene, which is characterized by developmental delay/intellectual disability, seizures, facial dysmorphism, short stature, and congenital malformations, primarily in the central nervous system, along with ophthalmic, dental, pulmonary, cardiologic, renal, gastrointestinal, and musculoskeletal anomalies. In this study, we describe the first Colombian patient with ZTT harboring a novel mutation that has not been previously reported and review the clinical and molecular features of previously reported patients in the literature.
Haploinsufficiency
Facial dysmorphism
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Haploinsufficiency
Speech delay
Global developmental delay
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Haploinsufficiency
DYRK1A
Febrile seizure
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Haploinsufficiency
Microcephaly
Facial dysmorphism
Subtelomere
Growth retardation
Global developmental delay
Long arm
Comparative genomic hybridization
Craniofacial abnormality
Speech delay
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The Mediator complex subunit 13-like is a part of the large Mediator complex. Recently, a large number of patients were diagnosed with mutations in this gene, which makes it one of the most frequent causes of syndromic intellectual disability. In this work, we report a patient with a novel de novo likely pathogenic variant c.5941C>T, p.(Gln1981*) in the MED13L gene with severe intellectual disability and facial dysmorphism. Uncommon findings like lack of speech, strabismus and self-destructive behaviour present in our patient allowed us to further define the phenotypic spectrum of mental retardation and distinctive facial features with or without cardiac defects syndrome.
Haploinsufficiency
Nonsense
Facial dysmorphism
Mediator
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Haploinsufficiency of BCL 11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome
Abstract Background Chromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability ( ID ), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature. Methods Molecular analysis was performed using microarray‐based comparative genomic hybridization (array CGH ). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed. Results We identified four patients with ID , neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL 11A , PAPOLG , and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons. Conclusion The zinc finger transcription factor BCL 11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL 11A haploinsufficiency is closely related to cerebellar abnormalities.
Haploinsufficiency
Microcephaly
Pons
Comparative genomic hybridization
Speech delay
Microdeletion syndrome
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