Background: Definition of the individual genotypes that cause a Mendelian phenotype is of great importance both to clinical diagnostics and disease characterization. Heterozygous de novo gain-of-function missense variants in RARB are associated with syndromic microphthalmia 12 (MCOPS12), a developmental disorder characterized by eye malformations and variable involvement of other organs. A subset of patients were described with poorly delineated movement disorders. Additionally, RARB bi-allelic loss-of-function variants, inherited from asymptomatic heterozygous carrier parents, have been found in a recessive family with four MCOPS12-affected members.
Patient/methods: We used trio whole-exome sequencing to explore the molecular basis of disease in an individual with congenital eye abnormality and movement disorder. All patients with reported RARB variants were reviewed.
Results: We report on identification of a heterozygous de novo RARB nonsense variant in a girl with microphthalmia and progressive generalized dystonia. Public database entries indicate that the de novo variant is recurrently present in clinically affected subjects but a literature report has not yet been available.
Conclusions: We provide the first detailed evidence for a role of dominant RARB truncating alterations in congenital eye-brain disease, expanding the spectrum of MCOPS12-associated mutations. Considered together with the published family with bi-allelic variants, the data suggest manifestation and non-manifestation of disease in relation to almost identical RARB loss-of-function variations, an apparent paradox that is seen in a growing number of human genetic conditions associated with both recessive and dominant inheritance patterns.
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http://dx.doi.org/10.1016/j.ejmg.2023.104802 | DOI Listing |
Psychiatr Genet
February 2025
Department of Obstetrics.
Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic disease characterized by growth retardation, psychomotor retardation, and distinctive facial features. It is primarily caused by mutations in CREBBP or EP300. In this study, we aimed to describe the clinical manifestations and genetic analyses of two cases with RSTS.
View Article and Find Full Text PDFAm J Med Genet A
January 2025
Department of Pediatric Genetics, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.
Hajdu-Cheney syndrome (HCS), caused by a heterozygous gain of function variant of the NOTCH2 gene, is a rare skeletal dysplasia. Although the main presentation is acro-osteolysis, osteoporosis, and facial dysmorphism, having a wide range of clinical manifestations creates diagnostic difficulties. Here, a 15-year-old male patient with HCS who had no complaints until this age except for two short bone fractures and one vertebral collapse fracture due to a fall was reported.
View Article and Find Full Text PDFNeuropediatrics
December 2024
Great Ormond Street Hospital for Children, London, United Kingdom of Great Britain and Northern Ireland.
We describe a set of monozygotic twins with GRIN2B-related neurodevelopmental disorder (GRIN2B-ND) who exhibited distinct clinical and imaging characteristics due to a de novo heterozygous pathogenic variant in the GRIN2B gene (c.2453T>C, p.Met818Thr).
View Article and Find Full Text PDFEur J Med Genet
December 2024
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan. Electronic address:
Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described.
View Article and Find Full Text PDFEur J Hum Genet
December 2024
Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene.
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