Whole exome sequencing in foetal akinesia expands the genotype–phenotype spectrum of GBE1 glycogen storage disease mutations

Ravenscroft, Gianina; Thompson, Elizabeth; Todd, Emily J.; Yau, Kyle S.; Kresoje, Nina; Sivadorai, Padma; Friend, Kathryn; Riley, K.; Manton, Nicholas; Blumbergs, Peter; Fietz, Michael; Duff, Rachael M.; Davis, Mark; Allcock, Richard; Laing, Nigel G.

doi:10.1016/j.nmd.2012.11.005

Cited by 39 publications

(31 citation statements)

References 22 publications

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“…Halder et al (12) reported a case in which twins carrying the 22q11.2DS microdeletion had discordant phenotypes with a different sized genetic deletion. Another technique, exome sequencing, offers an efficient and affordable method to investigate the genetic factors involved in human diseases (13)(14)(15)(16). B.D.…”

Section: Introductionmentioning

confidence: 99%

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

et al. 2015

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Abstract. Smith-Magenis syndrome (SMS) is a rare condition with multiple congenital malformations caused by the haploinsufficiency of RAI1 (deletion or mutation of RAI1). However, the correlation between genotype and phenotype is not well understood. The present study describes the prenatal diagnosis of monozygotic twins with a 17p11.2 deletion, which is indicative of SMS, who presented with discordant phenotypes and uteroplacental insufficiency. A high-resolution genome-wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in the 17p11.2 chromosome region. Accurate breakpoints of the deletion in these patients were used to identify correlations between SMS and the concomitant phenotypes, particularly uteroplacental insufficiency, which has rarely been investigated in SMS. In addition, no exonic mutations were identified in or affected known disease-associated loci that could explain the congenital anomalies, according to a model that accounts for the possibility of incomplete penetrance. Furthermore, a novel benign copy number variation (a duplication of 195 kb at 13q12.13) was identified but was unlikely to be clinically significant in the discordant phenotypes of the twins. The present study showed that multiple interacting genetic and environmental factors are involved in determining the variance of the SMS phenotype.

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Section: Introductionmentioning

confidence: 99%

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

et al. 2015

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“…Targeted capture and next generation sequencing (NGS) of 277 known and candidate neuromuscular disease causing genes (manuscript in preparation) were then performed. Bioinformatic analysis of the sequencing data used the previously published in‐house pipeline . Confirming the presence of the MYH2 variant and screening of relatives was done by Sanger sequencing.…”

Section: Patient and Methodsmentioning

confidence: 99%

“…Mutations in various genes were excluded as being causative, including facioscapulohumeral muscular dystrophy D4Z4 repeat contractions, large scale deletions of mitochondrial DNA, ANO5, calpain 3, collagens Targeted capture and next generation sequencing (NGS) of 277 known and candidate neuromuscular disease causing genes (manuscript in preparation) were then performed. Bioinformatic analysis of the sequencing data used the previously published in-house pipeline (13). Confirming the presence of the MYH2 variant and screening of relatives was done by Sanger sequencing.…”

Section: Genetic Analysismentioning

confidence: 99%

Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2

et al. 2015

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An MYH2 mutation p.(Glu706Lys) was originally described in a family with autosomal dominant inheritance, where the affected family members presented with multiple congenital contractures and ophthalmoplegia, progressing to a proximal myopathy in adulthood. Another patient with a dominant mutation p.(Leu1870Pro) was described, presenting as a congenital myopathy with ophthalmoplegia. Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia. Initially, clinically classified as oculopharyngodistal myopathy, the patient was found to carry a novel, de novo MYH2 mutation c.5630T>C p.(Leu1877Pro). This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum.

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“…Sibling 1: subtelomeric FISH using an in-house subtelomeric probe panel (methods available upon request), a G-banded karyotype at a resolution of 550 bands, Subsequently, exome enrichment was performed on DNA extracted from a peripheral blood sample from Sibling 1 using a TargetSeq V2 enrichment kit, as described previously [Ravenscroft et al, 2013] and paired-end (75 bp þ 35 bp) sequencing was performed on a SOLID 5500XL (Life Technologies, Carlsbad, CA) with an average read depth of 65Â, with 73% of the exome covered at >20Â, at the Lotterywest State Biomedical Facility Genomics node at Royal Perth Hospital. Sibling 1: subtelomeric FISH using an in-house subtelomeric probe panel (methods available upon request), a G-banded karyotype at a resolution of 550 bands, Subsequently, exome enrichment was performed on DNA extracted from a peripheral blood sample from Sibling 1 using a TargetSeq V2 enrichment kit, as described previously [Ravenscroft et al, 2013] and paired-end (75 bp þ 35 bp) sequencing was performed on a SOLID 5500XL (Life Technologies, Carlsbad, CA) with an average read depth of 65Â, with 73% of the exome covered at >20Â, at the Lotterywest State Biomedical Facility Genomics node at Royal Perth Hospital.…”

Section: Genetic Analysesmentioning

confidence: 99%

“…Subsequently, exome enrichment was performed on DNA extracted from a peripheral blood sample from Sibling 1 using a TargetSeq V2 enrichment kit, as described previously [Ravenscroft et al, 2013] and paired-end (75 bp þ 35 bp) sequencing was performed on a SOLID 5500XL (Life Technologies, Carlsbad, CA) with an average read depth of 65Â, with 73% of the exome covered at >20Â, at the Lotterywest State Biomedical Facility Genomics node at Royal Perth Hospital. After sequencing, reads were mapped and variants were called using Lifescope 2.5.1 (Life Technologies, Carlsbad, CA).…”

Section: Genetic Analysesmentioning

confidence: 99%

A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces

Baynam

Overkov

Davis

et al. 2015

American J of Med Genetics Pt A

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We report on three Aboriginal Australian siblings with a unique phenotype which overlaps with known megalencephaly syndromes and RASopathies, including Costello syndrome. A gain-of-function mutation in MTOR was identified and represents the first reported human condition due to a germline, familial MTOR mutation. We describe the findings in this family to highlight that (i) the path to determination of pathogenicity was confounded by the lack of genomic reference data for Australian Aboriginals and that (ii) the disease biology, functional analyses in this family, and studies on the tuberous sclerosis complex support consideration of an mTOR inhibitor as a therapeutic agent.

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Whole exome sequencing in foetal akinesia expands the genotype–phenotype spectrum of GBE1 glycogen storage disease mutations

Cited by 39 publications

References 22 publications

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2

A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces

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