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Am J Med Genet A. 2017 Oct;173(10):2763-2771. doi: 10.1002/ajmg.a.38375. Epub 2017 Aug 4.

Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.

Author information

1
GeneDx, Gaithersburg, Maryland.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
3
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Medical Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasilia-DF, Brazil.
5
Human Genetics Unit, Medical and Developmental Genetics, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom.
6
Department of Plastic & Reconstructive Surgery, Johns Hopkins Hospital University School of Medicine, Baltimore, Maryland.
7
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
8
Rare Disease Center, University of Tübingen, Tübingen, Germany.
9
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
10
Department of Clinical Genetics, University Medical Center, University of Utrecht, Utrecht, The Netherlands.
11
Department of Genetics-Hospital Robert DEBRE, Paris, France.
12
Dr. Angela Robles Pediatrics Private Practice, San Sebastian, Puerto Rico.
13
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
14
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
15
Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
16
Howard Hughes Medical Institution, Chevy Chase, Maryland.
17
Department of Pediatrics, University of Utah, Salt Lake City, Utah.
18
Greenberg Center for Skeletal Dysplasias, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Abstract

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

KEYWORDS:

Carey-Fineman-Ziter syndrome; Moebius syndrome; Myopathy; Native American Myopathy; Puerto Rican; Qatar; cleft palate; p.Trp284Ser variant

PMID:
28777491
PMCID:
PMC5843189
DOI:
10.1002/ajmg.a.38375
[Indexed for MEDLINE]
Free PMC Article

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