Intra-familial variability associated with recessive RYR1 mutation diagnosed prenatally by exome sequencing

Casey, Jillian P.; Flood, Karen; Ennis, Sean; Doyle, Evelyn; Farrell, Michael; Lynch, Sally Ann

doi:10.1002/pd.4925

Cited by 14 publications

(14 citation statements)

References 37 publications

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“…Ten of the 31 reports describe single cases and there were five small series of two to four cases . The larger studies of five or more cases present a range of inclusion criteria including termination of pregnancy or fetal demise with fetal anomalies, euploid fetuses with structural anomalies on ultrasound, increased nuchal translucency (NT) >3.5 mm, single or multiple fetal anomalies (Table ).…”

Section: Existing Prenatal Wes Studiesmentioning

confidence: 99%

Promises, pitfalls and practicalities of prenatal whole exome sequencing

et al. 2017

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Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-making and management. In several small series, prenatal whole exome sequencing (WES) approaches have identified genetic diagnoses when conventional tests (karyotype and microarray) were not diagnostic. Here, we review published prenatal WES studies and recent conference abstracts. Thirty-one studies were identified, with diagnostic rates in series of five or more fetuses varying between 6.2% and 80%. Differences in inclusion criteria and trio versus singleton approaches to sequencing largely account for the wide range of diagnostic rates. The data suggest that diagnostic yields will be greater in fetuses with multiple anomalies or in cases preselected following genetic review. Beyond its ability to improve diagnostic rates, we explore the potential of WES to improve understanding of prenatal presentations of genetic disorders and lethal fetal syndromes. We discuss prenatal phenotyping limitations, counselling challenges regarding variants of uncertain significance, incidental and secondary findings, and technical problems in WES. We review the practical, ethical, social and economic issues that must be considered before prenatal WES could become part of routine testing. Finally, we reflect upon the potential future of prenatal genetic diagnosis, including a move towards whole genome sequencing and non-invasive whole exome and whole genome testing.

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Section: Existing Prenatal Wes Studiesmentioning

confidence: 99%

Promises, pitfalls and practicalities of prenatal whole exome sequencing

et al. 2017

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“…Mutations in these channels have been linked to the pharmacogenetic condition of malignant hyperthermia, to hypokalemic periodic paralysis, and to a spectrum of myopathies [ 22 ]. The often prenatal onset of the latter [ 23 ] implies important functions of the two Ca 2+ channels in myogenesis.…”

Section: Introductionmentioning

confidence: 99%

Distinct transcriptomic changes in E14.5 mouse skeletal muscle lacking RYR1 or Cav1.1 converge at E18.5

et al. 2018

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In skeletal muscle the coordinated actions of two mechanically coupled Ca2+ channels—the 1,4-dihydropyridine receptor (Cav1.1) and the type 1 ryanodine receptor (RYR1)–underlie the molecular mechanism of rapid cytosolic [Ca2+] increase leading to contraction. While both [Ca2+]i and contractile activity have been implicated in the regulation of myogenesis, less is known about potential specific roles of Cav1.1 and RYR1 in skeletal muscle development. In this study, we analyzed the histology and the transcriptomic changes occurring at E14.5 –the end of primary myogenesis and around the onset of intrauterine limb movement, and at E18.5 –the end of secondary myogenesis, in WT, RYR1-/-, and Cav1.1-/- murine limb skeletal muscle. At E14.5 the muscle histology of both mutants exhibited initial alterations, which became much more severe at E18.5. Immunohistological analysis also revealed higher levels of activated caspase-3 in the Cav1.1-/- muscles at E14.5, indicating an increase in apoptosis. With WT littermates as controls, microarray analyses identified 61 and 97 differentially regulated genes (DEGs) at E14.5, and 493 and 1047 DEGs at E18.5, in RYR1-/- and Cav1.1-/- samples, respectively. Gene enrichment analysis detected no overlap in the affected biological processes and pathways in the two mutants at E14.5, whereas at E18.5 there was a significant overlap of DEGs in both mutants, affecting predominantly processes linked to muscle contraction. Moreover, the E18.5 vs. E14.5 comparison revealed multiple genotype-specific DEGs involved in contraction, cell cycle and miRNA-mediated signaling in WT, neuronal and bone development in RYR1-/-, and lipid metabolism in Cav1.1-/- samples. Taken together, our study reveals discrete changes in the global transcriptome occurring in limb skeletal muscle from E14.5 to E18.5 in WT, RYR1-/- and Cav1.1-/- mice. Our results suggest distinct functional roles for RYR1 and Cav1.1 in skeletal primary and secondary myogenesis.

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“…In these patients decreased fetal movements, arthrogryposis multiplex congenita (AMC), polyhydramnios, scoliosis and respiratory distress are typically observed [1,[3][4]19]. Recently, several cases with a lethal neonatal course have been documented [20], some of those within the spectrum of the "lethal multiple pterygium syndrome" [5]. Intrafamilial phenotypic variability has been reported in several families affected by such severe presentations [4,20].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several cases with a lethal neonatal course have been documented [20], some of those within the spectrum of the "lethal multiple pterygium syndrome" [5]. Intrafamilial phenotypic variability has been reported in several families affected by such severe presentations [4,20].…”

Section: Introductionmentioning

confidence: 99%

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding

Brackmann

Türk

Gratzki

et al. 2018

Neuromuscular Disorders

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RYR1 mutations, the most common cause of non-dystrophic neuromuscular disorders, are associated with the malignant hyperthermia susceptibility (MHS) trait as well as congenital myopathies with widely variable clinical and histopathological manifestations. Recently, bleeding anomalies have been reported in association with certain RYR1 mutations. Here we report a preterm infant born at 32 weeks gestation with arthrogryposis multiplex congenita due to compound heterozygous, previously MHS-associated RYR1 mutations, with additional signs of prenatal hemorrhage. The patient presented at birth with multiple joint contractures, scoliosis, severe thoracic rigidity and respiratory failure. He continued to depend on mechanical ventilation and tube feeding. Muscle histopathology showed a marked myopathic pattern with eccentric cores. Interestingly, the patient had additional unusual prenatal intraventricular hemorrhage, resulting in post-hemorrhagic hydrocephalus as well as epidural hemorrhage affecting the spinal cord. This report adds to the phenotypic variability associated with RYR1 mutations, and highlights possible bleeding complications in affected individuals.

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Intra-familial variability associated with recessive RYR1 mutation diagnosed prenatally by exome sequencing

Cited by 14 publications

References 37 publications

Promises, pitfalls and practicalities of prenatal whole exome sequencing

Promises, pitfalls and practicalities of prenatal whole exome sequencing

Distinct transcriptomic changes in E14.5 mouse skeletal muscle lacking RYR1 or Cav1.1 converge at E18.5

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding

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