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.

STAC3variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

“…One patient with severe presentation (PN5) was compound heterozygous for the recurrent NAM and a novel splice site variant. Similarly, three other reported previously patients with a more severe phenotype carried variants other than the recurrent NAM variant (frameshift or splice site variants; Grzybowski et al, 2017;Telegrafi et al, 2017). However, it is worth noting that a degree of clinical variability is also observed among patients with homozygous NAM variant and among members of the same family, suggesting that factors other than the type of variants could contribute to the phenotypic variability.…”

“…The observation of the NAM variant in various populations often of African descent could point toward a common ancestor of possible African origin. Interestingly, Telegrafi et al (2017) found that the NAM variant was not in linkage with the same haplotype in their two families, implying that these variants originated from unrelated mutational events. Further studies and haplotype analysis might help to further clarify this point.…”

“…NAM is an autosomal recessive disorder found in the Lumbee Indian population of North Carolina and characterized by congenital muscle weakness, delayed motor development, susceptibility to malignant hyperthermia (MH), multiple joint contractures, short statue, scoliosis, and distinctive facial features such as ptosis, palate abnormalities, and long and narrow face (Stamm et al., ). Recently, recessive variants in STAC3 have been reported in patients with features overlapping Carey–Fineman–Ziter and Moebius syndrome (Grzybowski et al., ; Telegrafi et al., ).…”

“…Recently, recessive variants in STAC3 have been reported in patients with features overlapping Carey-Fineman-Ziter and Moebius syndrome (Grzybowski et al, 2017;Telegrafi et al, 2017).…”

Whole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome

“…Distinguishing features of STAC3 -CFZS are short stature and malignant hyperthermia. 7 Whether other clinical features present in our patient are a consequence of MYMK mutations remains to be established through continued follow-up of the known patients 6 and diagnosis and follow-up of new patients with CFZS.…”