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

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.

Conflict of interest statement

Conflict of Interest:

Aida Telegrafi is an employee of GeneDx, Inc. The other authors have no conflicts to declare.

© 2017 Wiley Periodicals, Inc.

Figures

Figure 1

Informed consent for photograph use was obtained. A) Proband is symmetrically small for age with scoliosis and asymmetric hip position. B) C) and D) long face with dolichocephaly, myotonic facies, downslanting palpebral fissures with severe ptosis, tented upper lip, downturned corners of the mouth. E) decreased skin creases over distal interphalangeal joints and wrists

Figure 2

Informed consent for photographs was obtained. A) The proband is noted to have significant short stature. Head is normocephalic. B,C) The proband has a long face with bitemporal narrowing, midface hypoplasia, downslanting palpebral fissures, bilateral epicanthal folds, ptosis, low-set and posteriorly rotated ears, and hypoplastic nasolabial folds. D) Camptodactyly is noted at the DIP joint of the 5th digit. Decreased skin creases are noted at the DIP joint of all digits. E) The proband’s sister has significant short stature and a tracheostomy. F–G) Head is brachycephalic. She has a long face with bitemporal narrowing, midface hypoplasia, downslanting palpebral fissures, bilateral epicanthal folds, and ptosis. H) Feet are notable for brachydactyly, overlapping toes, and hypoplasia of metatarsals 2 through 5.

Figure 3

A. Family history is significant for 18-year-old similarly affected sister and parental consanguinity in a family form Qatar. A maternal uncle had 4 male children with neonatal deaths of unknown etiology from a consanguineous union. The same maternal uncle had 6 healthy children. Note, the presence of the star indicates that DNA samples of these individuals were available for testing. The black circles represent the clinically affected individuals with Native American Myopathy (NAM). Genotypes of the family members indicate biallelic variants in the two affected sisters with NAM, and the heterozygous state of the parents and the unaffected brothers. B. Family history is notable for two affected siblings born from a noncosanguineous union. Maternal and paternal lineages are of Puerto Rican ancestry. Genotypes of the family members indicate biallelic variants in the two affected siblings with NAM.