The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent variants in the U4 RNA, transcribed from the gene, and in at least two other genes were discovered to cause neurodevelopmental disorder.
View Article and Find Full Text PDFOsteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant sclerosing osteodysplasia, due to AMER1 pathogenic variants. Characteristic features include craniofacial sclerosis and long-bone metaphyseal striations. Moyamoya disease (a type of progressive cerebral vasculopathy) and other types of cerebral vascular disease are not currently clearly associated with OSCS (except for two separate case reports), and can often first present with stroke.
View Article and Find Full Text PDFBackground: Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 () gene have been identified to cause OSMD.
View Article and Find Full Text PDFAutozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (F) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of F.
View Article and Find Full Text PDFPurpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases.
Purpose: This study aimed to investigate whether a bioinformatics application can streamline genome reanalysis and yield new diagnoses for patients with rare diseases.
Methods: We developed TierUp to identify variants in new disease genes for unresolved rare disease cases recruited to the 100,000 Genomes Project, all of whom underwent genome sequencing. TierUp uses the NHS Genomic Medicine Service bioinformatics infrastructure by securely accessing case details from the Clinical Interpretation Portal application programming interface and by querying the curated PanelApp database for novel gene-disease associations.
Br Med Bull
September 2021
Background: Genetic skeletal dysplasia conditions (GSDs) account for 5% of all birth defects. Until recently, targeted treatments were only available for select few conditions; 1 however, opportunities arising from developments in molecular diagnostic technologies are now leading to unparalleled therapeutic advances. This review explores current GSD clinical trials, their challenges and the hopes for the future.
View Article and Find Full Text PDFKIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
View Article and Find Full Text PDFThe congenital imprinting disorder, Beckwith-Wiedemann syndrome (BWS) is associated with variable clinical features including hemihypertrophy/lateralised overgrowth (LO) and embryonal tumour predisposition. BWS-associated (epi)genetic alterations occur in a subset of patients with isolated LO (ILO), leading to the concept of BWS spectrum disorder (BWSp). We investigated the relationship between clinical features and molecular diagnostic results in a cohort with LO using the BWSp international consensus group (BWSICG) clinical scoring system.
View Article and Find Full Text PDFA 4-year-old boy presented with his mother to genetics in the 1980s, with a family history (FH) of macrocephaly and intellectual disability (ID). He remained undiagnosed until his mother developed multiple cancers and was diagnosed with Cowden syndrome (CS) in 2017, a rare, multisystem cancer predisposition syndrome. CS was then confirmed in multiple family members.
View Article and Find Full Text PDFWe report a further case of spondylometaphyseal dysplasia - corner fracture type due to the fibronectin-1 gene (SMD-FN1) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation.
View Article and Find Full Text PDFERBB4 encodes the tyrosine kinase receptor HER4, a critical regulator of normal cell function and neurodevelopmental processes in the brain. One of the key ligands of HER4 is neureglin-1 (NRG1), and the HER4-NRG1 signalling pathway is essential in neural crest cell migration, and neuronal differentiation. Pharmacological inactivation of HER4 has been shown to hasten the progression of epileptogenesis in rodent models, and heterozygous ERBB4 null mice are shown to have cognitive deficits and delayed motor development.
View Article and Find Full Text PDFBone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants).
View Article and Find Full Text PDFSignal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
View Article and Find Full Text PDFHypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.
View Article and Find Full Text PDFWolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement.
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