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- Baskin, Berivan, et al.
(författare)
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Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms
- 2014
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley-Blackwell. - 2324-9269. ; 2:6, s. 539-547
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Tidskriftsartikel (refereegranskat)abstract
- Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2–5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45–49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
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- Chorin, Odelia, et al.
(författare)
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Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis
- 2020
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Ingår i: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA-based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole-genome sequencing was nondiagnostic. Methods: We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies. Results: We identified a pathogenic deep intronic variant in CLCN7 creating an unexpected, frameshifting pseudoexon causing complete loss of function. Functional studies, including osteoclastogenesis and bone resorption assays, confirmed normal osteoclast differentiation but loss of osteoclast function. Conclusion: This is the first report of a pathogenic deep intronic variant in CLCN7, and our approach provides a model for systematic identification of noncoding variants causing osteopetrosis—a disease for which molecular-genetic diagnosis can be pivotal for potentially curative hematopoietic stem cell transplantation. Our work illustrates that cryptic splice variants may elude DNA-only sequencing and supports broad first-line use of transcriptome sequencing for children with undiagnosed diseases.
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- Clewemar, Pantelis, et al.
(författare)
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Expanding the phenotypic spectrum of osteogenesis imperfecta type V including heterotopic ossification of muscle origins and attachments
- 2019
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOsteogenesis imperfecta (OI) is a clinical and genetic heterogeneous group of connective tissue disorders, characterized by bone fragility and a propensity to fracture.MethodsIn this report we describe the clinical phenotype of two patients, a 28‐year‐old woman and her mother (54 years old), both with a history of short stature and multiple fractures.ResultsExome sequencing revealed the recurring IFITM5:c.‐14 C>T variant causing OI type V. Both patients had several fractures during childhood. CT‐scan and scintigraphy showed ossification of the origin and attachment of muscles and hypertrophic callus formation.ConclusionOssification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V.
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- Dobloug, Sigurd, et al.
(författare)
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Maculopathy and adult-onset ataxia in patients with biallelic MFSD8 variants
- 2024
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Ingår i: Molecular Genetics and Genomic Medicine. - 2324-9269. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult-onset retinal dystrophy. Classic late-infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non-syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. Methods: Here we present longitudinal studies on four adult-onset patients who were biallelic for four MFSD8 variants. Results: Two unrelated patients who presented with adult-onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. Conclusions: Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8-related disease, adult-onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.
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- Dominguez, Mev, et al.
(författare)
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Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein.
- 2014
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:4, s. 352-355
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Tidskriftsartikel (refereegranskat)abstract
- In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.
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- Engström, Karolina, et al.
(författare)
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Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection
- 2020
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Ingår i: Molecular Genetics & Genomic Medicine. - : John Wiley & Sons. - 2324-9269. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pathogenic variants in the SMAD3 gene affecting the TGF-beta/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome.Methods: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.Results: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta.Conclusion: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.
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