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Case Reports
. 2024 May 27;15(6):699.
doi: 10.3390/genes15060699.

Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies

Paulina Ocieczek  1   2 , Ngozi Oluonye  1   3 , Cécile Méjécase  2   4 , Elena Schiff  1 , Vijay Tailor  1   2 , Mariya Moosajee  1   2   3   4
Affiliations
Case Reports

Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies

Paulina Ocieczek et al. Genes (Basel). .

Abstract

Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The MYF5 gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in MYF5 were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in MYF5 have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous MYF5 frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four MYF5 variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.

Keywords: MYF5; external ophthalmoplegia; external ophthalmoplegia with vertebral and rib anomalies (EORVA); myogenic factor 5; myogenic transcription factors; rib anomalies; scoliosis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The role of myogenic transcription factors in extraocular myogenesis in mice. Extraocular muscles (EOM) are derived from cranial mesoderm progenitors. Expression of either Myf5 or Mrf4 is required for EOM progenitor cells to acquire their myogenic fate. Myf5 or Mrf4 activates MyoD, which in turn activates MyoG and EOM differentiation. Created with Biorender.
Figure 2
Figure 2
Family pedigree—three siblings from a consanguineous Pakistani family are affected with external ophthalmoplegia, with vertebral and rib anomalies. Square symbols indicate males; circles indicate females. Diamonds represent either gender. The number inside the shape is the number of individuals. Filled symbols are affected individuals. The black arrow indicates the proband.
Figure 3
Figure 3
(A) Facial photo; (B) dental photo; (C) Patient IV-1 skeletal X-ray, antero-posterior view- mild thoracic scoliosis centred at T6-T7 concave to the left; (D) Patient IV-1 skeletal X-ray, lateral (L) view; gaze position photos (N.B. not all positions of gaze were obtained due to ptosis obscuring eye position); (E) dextro-elevation; (F) direct elevation; (G) laevo elevation; (H) primary position; (I) laevo version; (J) MRI orbits Patient IV-1: left medial rectus, left superior rectus, and left superior oblique muscles smaller comparing to respective EOMs in the right eye; (K) colour fundus photo; (L) autofluorescence photo; (M) macular OCT.
Figure 4
Figure 4
Mutational spectrum of MYF5 related external ophthalmoplegia, with vertebral and rib anomalies. (A) Variants previously described depicted across exon 1 of MYF5 gene (NM_005593.3), while the novel disease-causing variant reported in this study is located in exon 3. (B) Amino acid changes mapped across MYF5 transcription factor (NP_005584, UniProt P13349); bHLH-basic helix–loop–helix protein domain (amino acid residue 83 to 134) binding DNA. The novel disease-causing variant reported in this study is indicated in bold. Asterisk (*) indicates premature termination (stop) codon.
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