Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum

被引:17
作者
Alkhunaizi, Ebba [1 ,2 ]
Shuster, Shirley [1 ]
Shannon, Patrick [3 ]
Siu, Victoria Mok [4 ]
Darilek, Sandra [5 ]
Mohila, Carrie A. [6 ,7 ]
Boissel, Sarah [8 ]
Ellezam, Benjamin [8 ]
Fallet-Bianco, Catherine [9 ]
Laberge, Anne-Marie [8 ]
Zandberg, Julianne [4 ]
Injeyan, Marie [1 ]
Hazrati, Lili-Naz [10 ]
Hamdan, Fadi [8 ]
Chitayat, David [1 ,2 ]
机构
[1] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Ontario Power Generat Bldg,700 Univ Ave,Rm 3-709, Toronto, ON M5G 1Z5, Canada
[2] Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Dept Pediat, Toronto, ON, Canada
[3] Univ Toronto, Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON, Canada
[4] Western Univ, London Hlth Sci Ctr, Schulich Sch Med & Dent, Div Med Genet,Dept Pediat, London, ON, Canada
[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[6] Texas Childrens Hosp, Dept Pathol, Houston, TX 77030 USA
[7] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
[8] CHU St Justine, Res Ctr, Dept Med Genet, Montreal, PQ, Canada
[9] CHU St Justine, Dept Pathol, Montreal, PQ, Canada
[10] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
关键词
arthrogryposis multiplex congenita; fetal akinesia deformation sequence syndrome; lethal multiple pterygium syndrome; malignant hyperthermia; RYR1; CENTRAL CORE DISEASE; LARGE COHORT; MUTATIONS; MYOPATHIES; SEQUENCE; RELEASE; CA2+;
D O I
10.1002/ajmg.a.61025
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.
引用
收藏
页码:386 / 396
页数:11
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