Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology

Abstract Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015–2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

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Autosomal Recessive Limb Girdle Muscular Dystrophy In A Complex Consanguineous Family: The First Cases Series In Indonesia

Journal of Biomedicine and Translational Research ◽

10.14710/jbtr.v3i2.1500 ◽

2017 ◽

Vol 3 (2) ◽

pp. 26

Author(s):

Nydia Rena Benita Sihombing ◽

Nurin Aisyiyah Listyasari ◽

Sultana MH Faradz

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Snp Array ◽

Large Family ◽

Limb Girdle Muscular Dystrophy ◽

Immunoperoxidase Staining ◽

Chromosome 15 ◽

Large Pedigree ◽

Abnormal Gait ◽

Recessive Type

ABSTRACTBackground: Limb girdle muscular dystrophy (LGMD) is a neuromuscular abnormality with clinical heterogeneity and various severity, where over 30 subtypes have been identified. Meanwhile, molecular diagnosis of LGMD is not commonly carried out in Indonesia. We present a large pedigree of familial LGMD, with over 14 years of follow-up.Case Presentation: A 12-year old female patient came with muscle weakness. She had toe walking since age of 6, followed by calf hypertrophy for over three years. Family history revealed complex consanguinity. Her younger sister and her parents’ cousin had similar condition, with the latter was already bedridden.Physical examination results were waddling gait, lordotic spine, and absent deep tendon reflexes. Muscle biopsy showed sign of dystrophic process. Immunoperoxidase staining of some proteins resulted normal. Single nucleotide polymorphism (SNP) array in two siblings revealed homozygosity on chromosome 15 containing CAPN3 gene of LGMD2A subtype.Recently, the patient is wheelchair bound and undergoes rehabilitation. Her sister is still able to walk with abnormal gait, while her parents’ cousin had passed away in age 55. From the multiple consanguinity, it could be concluded as autosomal recessive type LGMD.Conclusion: A large family with LGMD from Indonesia was presented with more than 14 years of care. Clinical diagnosis was made based on physical and additional examination, however molecular analysis for establishing definitive diagnosis is still limited. Further studies such as targeted or whole exome sequencing is warranted to elucidate the cause of disease. Long-term evaluation and supportive care, in addition to proper counseling may increase quality of life.

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Mosaic maternal uniparental disomy of chromosome 15 in Prader-Willi syndrome: Utility of genome-wide SNP array

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.35625 ◽

2012 ◽

Vol 161 (1) ◽

pp. 166-171 ◽

Cited By ~ 11

Author(s):

Kosuke Izumi ◽

Avni B. Santani ◽

Matthew A. Deardorff ◽

Holly A. Feret ◽

Tanya Tischler ◽

...

Keyword(s):

Snp Array ◽

Uniparental Disomy ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Maternal Uniparental Disomy ◽

Genome Wide

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Maternal uniparental disomy of chromosome 4 and homozygous novel mutation in the WFS1 gene in a paediatric patient with Wolfram syndrome

Diabetes & Metabolism ◽

10.1016/j.diabet.2015.06.003 ◽

2015 ◽

Vol 41 (5) ◽

pp. 433-435 ◽

Cited By ~ 6

Author(s):

D.T. Papadimitriou ◽

E. Manolakos ◽

C. Bothou ◽

G. Zoupanos ◽

I. Papoulidis ◽

...

Keyword(s):

Paediatric Patient ◽

Novel Mutation ◽

Uniparental Disomy ◽

Wolfram Syndrome ◽

Chromosome 4 ◽

Maternal Uniparental Disomy ◽

Wfs1 Gene

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Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105463 ◽

2018 ◽

Vol 56 (6) ◽

pp. 413-418 ◽

Cited By ~ 8

Author(s):

Takanobu Inoue ◽

Hideaki Yagasaki ◽

Junko Nishioka ◽

Akie Nakamura ◽

Keiko Matsubara ◽

...

Keyword(s):

Snp Array ◽

Uniparental Disomy ◽

Gene Mutations ◽

Growth Failure ◽

Postnatal Growth ◽

Differentially Methylated Region ◽

Unknown Aetiology ◽

Chromosome 16 ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

BackgroundRecently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.ObjectiveTo clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.MethodsWe studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.ResultsWe identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.ConclusionWe suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.

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Maternal uniparental disomy of chromosome 4

10.32388/prkgv9 ◽

2020 ◽

Author(s):

Keyword(s):

Uniparental Disomy ◽

Chromosome 4 ◽

Maternal Uniparental Disomy

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High-Resolution Molecular Allelokaryotyping of Chronic Myeloid Leukemia Patients in Blast Crisis by 6.0 SNP-Arrays Shows a High-Frequency of Uniparental Disomy and Focal Copy Number Alterations Affecting the Whole Sequence or Specific Exons of Oncogenes and Tumor Suppressor Genes.

Blood ◽

10.1182/blood.v114.22.2176.2176 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2176-2176

Author(s):

Simona Soverini ◽

Sabrina Colarossi ◽

Alessandra Gnani ◽

Fausto Castagnetti ◽

Annalisa Astolfi ◽

...

Keyword(s):

High Resolution ◽

Tumor Suppressors ◽

Copy Number ◽

Myeloid Leukemia ◽

Blast Crisis ◽

Snp Array ◽

Uniparental Disomy ◽

Copy Number Alterations ◽

Snp Arrays ◽

Array Technology

Abstract Abstract 2176 Poster Board II-153 Progression from chronic phase to blast crisis (BC) remains a major hurdle on the road to effective treatment of chronic myeloid leukemia (CML). BC is known to be associated with accumulation of additional genetic alterations, but these alterations have so far been only partially characterized. The development of SNP-arrays as a tool for high-resolution karyotyping now allows to perform high-throughput genome-wide screens for submicroscopic genomic alterations with unprecedented informativity and resolution and to precisely map all the genes involved in these alterations. We have used Human 6.0 SNP Arrays (Affymetrix) to perform high-resolution molecular allelokaryotyping of 25 DNA samples from BC (myeloid, n=16; lymphoid, n=9) CML patients (pts). The 6.0 SNP Array technology relies on 1.8 million markers evenly spaced across the genome, with a median inter-marker distance <700 bp. Loss of Heterozygosity (LOH) analysis identified several recurrent regions of uniparental disomy (UPD) ranging from 970Kb to 2.4Mb: 3p21.31-3p21.2 (19 pts); 4p15.1 (n=18 pts); 14q23.3 (n=18 pts); 8q22.2 (n=15 pts); 7q31.31 (n=14 pts); 3q11.2 (13 pts); 17q23.2 (n=13 pts); 12q24.11-12q24.13 (n=12 pts); 15q15.2-15q15.3 (n=12 pts); 16q22.1 (n=12 pts); 10q22.1-10q22.2 (n=11 pts); 1p34.3 (n=10pts); 7q11.22 (n=10 pts); 8p11.12 (n=10 pts); 15q23-15q24.1 (n=9 pts); 20q11.22-20q11.23 (n=7 pts); 16q11.2 (n=6 pts); 17q11.2 (n=5 pts). Three pts had evidence of UPD involving the whole long arm of chromosomes 5, 14 and 19, respectively. Macroscopic copy number alterations (CNAs) (+8, +19, +14q; +21q; -7; -18, -16q; -17p; -6p; -6q; -9q) were frequent and easily detected. A variety of submicroscopic CNAs were also detected. However, we decided to exploit the unprecedented resolution power of Human 6.0 SNP Arrays and the ability of Genotyping Console 3.0.2 (Affymetrix) software to precisely pinpoint the borders of these CNAs. We thus aimed our analysis to the identification of very small CNAs that may have been missed by previous studies - all using less sensitive assays. This approach revealed a high number of focal gains or losses ranging from 4 to 47Kb, affecting single genes or even some exons only. Genes involved in >2 pts are listed in the Table below. Gains/losses mapping to known regions of copy number variation (CNV) were excluded. All the genes found to harbor CNAs were transcription factors, adaptor proteins, receptor and non-receptor kinases involved in cell proliferation and apoptosis - with a known role as oncogenes or tumor suppressors or oncogene/tumor suppressor interactors. Although these results confirm a high degrees of heterogeneity in the alterations detectable in BC CML pts, members of the RAS pathway (indicated with an asterisk) were the most frequently altered genes. Further characterization by polymerase chain reaction and sequencing is ongoing. In conclusion, the power of 6.0 SNP Array technology allowed us to detect previously unidentified alterations targeting whole or part of key oncogenes or tumor suppressors whose deregulation may play a role in determining the aggressive phenotype of BC CML, and which may represent potential therapeutic targets. Supported by European LeukemiaNet, AIL, AIRC, PRIN, Fondazione del Monte di Bologna e Ravenna. Disclosures: No relevant conflicts of interest to declare.

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A Novel Genetic Variant in the WFS1 Gene in a Patient with Partial Uniparental Mero-Isodisomy of Chromosome 4

International Journal of Molecular Sciences ◽

10.3390/ijms22158082 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8082

Author(s):

Maurizio Delvecchio ◽

Federica Ortolani ◽

Orazio Palumbo ◽

Concetta Aloi ◽

Alessandro Salina ◽

...

Keyword(s):

Diabetes Mellitus ◽

Genetic Variant ◽

Novel Mutation ◽

Blood Glucose Control ◽

Snp Array ◽

Uniparental Disomy ◽

Wolfram Syndrome ◽

Chromosome 4 ◽

Rapid Reduction ◽

First Case

Wolfram syndrome is a rare autosomal recessive disorder characterized by optic atrophy and diabetes mellitus. Wolfram syndrome type 1 (WFS1) is caused by bi-allelic pathogenic variations in the wolframin gene. We described the first case of WFS1 due to a maternal inherited mutation with uniparental mero-isodisomy of chromosome 4. Diabetes mellitus was diagnosed at 11 years of age, with negative anti-beta cells antibodies. Blood glucose control was optimal with low insulin requirement. No pathogenic variations in the most frequent gene causative of maturity-onset diabetes of the young subtypes were detected. At 17.8 years old, a rapid reduction in visual acuity occurred. Genetic testing revealed the novel homozygous variant c.1369A > G; p. Arg457Gly in the exon 8 of wolframin gene. It was detected in a heterozygous state only in the mother while the father showed a wild type sequence. In silico disease causing predictions performed by Polyphen2 classified it as “likely damaging”, while Mutation Tester and Sift suggested it was “polymorphism” and “tolerated”, respectively. High resolution SNP-array analysis was suggestive of segmental uniparental disomy on chromosome 4. In conclusion, to the best of our knowledge, we describe the first patient with partial uniparental mero-isodisomy of chromosome 4 carrying a novel mutation in the wolframin gene. The clinical phenotype observed in the patient and the analysis performed suggest that the genetic variant detected is pathogenetic.

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Sarcoglycan A Mutation in Miniature Dachshund Dogs Causes Limb Girdle Muscular Dystrophy 2D

10.21203/rs.3.rs-82758/v1 ◽

2020 ◽

Author(s):

James R Mickelson ◽

Katie M Minor ◽

Ling T Guo ◽

Steven G Friedenberg ◽

Jonah N Cullen ◽

...

Keyword(s):

Muscular Dystrophy ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Western Blotting ◽

Snp Array ◽

Elevated Serum ◽

Premature Stop Codon ◽

Limb Girdle Muscular Dystrophy ◽

Exercise Intolerance ◽

Whole Genome

Abstract BackgroundA cohort of related miniature dachshund dogs with exercise intolerance, stiff gait, dysphagia, myoglobinuria and markedly elevated serum creatine kinase activities were identified. MethodsMuscle biopsy histopathology, immunofluorescence microscopy, and western blotting, were combined to identify the specific pathologic phenotype of the myopathy, and whole genome SNP array genotype data and whole genome sequencing were combined to determine its genetic basis.ResultsMuscle biopsies were dystrophic. Sarcoglycanopathy, a form of limb-girdle muscular dystrophy, was suspected based on immunostaining and western blotting, where α, β, and γ-sarcoglycan were all absent or reduced. Genetic mapping and whole genome sequencing identified a premature stop codon mutation in the sarcoglycan A subunit gene ( SGCA ). Affected dachshunds were confirmed on several continents. ConclusionsThis first SGCA mutation found in dogs adds to the literature of genetic bases of canine muscular dystrophies and their usefulness as comparative models of human disease.

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