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Neurogenetics Jul 2023Unlike the 1p36 microdeletion syndrome, which has been extensively described, 1p36.3 microduplications have rarely been reported. We report the two siblings of familial...
Unlike the 1p36 microdeletion syndrome, which has been extensively described, 1p36.3 microduplications have rarely been reported. We report the two siblings of familial 1p36.3 microduplication, presenting with a severe global developmental delay, epilepsy, and a few dysmorphic features. They were referred to moderate-to-severe developmental delay (DD) and intellectual disability (ID). Both were considered eyelid myoclonus with absence of epilepsy (Jeavons syndrome). The EEG is characterized by widespread 2.5-3.5 Hz spikes and spike slow complex wave, eye closure sensitivity, and photosensitivity. The children has same dysmorphic features, including mild bitemporal narrowing and sloping forehead, sparse eyebrows, hypertelorism, ptosis, strabismus, infraorbital creases, wide nasal bridge with bulbous nasal tip, dystaxia, hallux valgus, and flat feet. Family exome sequencing revealed a maternally inherited 3.2-Mb microduplication of chromosomal band 1p36.3p36.2. However, DNA purified from blood samples of either parent did not find evidence for a microduplication of 1p36 in somatic tissue, indicating that such a mutation might be carried in the germline of the parents as gonadal mosaicism. No other family members of the affected siblings' parents were reported to be affected by the symptoms found.
Topics: Child; Humans; Intellectual Disability; Mutation; Epilepsy; Developmental Disabilities
PubMed: 37289317
DOI: 10.1007/s10048-023-00722-y -
Genes Aug 2023Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group... (Review)
Review
Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in , which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in . Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.
Topics: Humans; DNA Helicases; Histones; Hypertelorism; Intellectual Disability; Language Development Disorders; Megalencephaly; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Developmental Disabilities
PubMed: 37761804
DOI: 10.3390/genes14091664 -
Clinical Genetics Jul 2023PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in...
PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.
Topics: Humans; Dwarfism; Hedgehog Proteins; Osteochondrodysplasias; Prevalence; RNA Splice Sites
PubMed: 36896672
DOI: 10.1111/cge.14324