June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
SGMS2 mutation in a large Filipino family with calvarial doughnut lesions with bone fragility and juvenile-onset open angle glaucoma
Author Affiliations & Notes
  • Edward Ryan Collantes
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Jewel Faith Flores-Anotado
    Western Visayas Medical Center, Philippines
  • Ma Carmela Guevarra
    University of the East Ramon Magsaysay Memorial Medical Center Inc, Quezon City, Philippines
  • Arianne Dumdum
    Western Visayas Medical Center, Philippines
  • Janine Futolan
    Western Visayas Medical Center, Philippines
  • Maria Hannah Pia de Guzman
    Western Visayas Medical Center, Philippines
  • Barbara Joy Hidalgo
    Western Visayas Medical Center, Philippines
  • Vincent Paul Guzman
    Western Visayas Medical Center, Philippines
  • Karen Rivera-Francia
    Western Visayas Medical Center, Philippines
  • Janey L Wiggs
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Edward Ryan Collantes None; Jewel Faith Flores-Anotado None; Ma Carmela Guevarra None; Arianne Dumdum None; Janine Futolan None; Maria Hannah Pia de Guzman None; Barbara Joy Hidalgo None; Vincent Paul Guzman None; Karen Rivera-Francia None; Janey Wiggs None
  • Footnotes
    Support  NIH/NEI EY031820
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4019 – A0361. doi:
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      Edward Ryan Collantes, Jewel Faith Flores-Anotado, Ma Carmela Guevarra, Arianne Dumdum, Janine Futolan, Maria Hannah Pia de Guzman, Barbara Joy Hidalgo, Vincent Paul Guzman, Karen Rivera-Francia, Janey L Wiggs; SGMS2 mutation in a large Filipino family with calvarial doughnut lesions with bone fragility and juvenile-onset open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4019 – A0361.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : SGMS2 (sphingomyelin synthase 2 (SMS2)) pathogenic variants cause a rare autosomal dominant skeletal disorder with characteristic skull lesions known as Calvarial Doughnut Lesions with Bone Fragility (CDL) (MIM 12655). A recurrent nonsense mutation (c.148 C>T,p.Arg50*) has been found in 4 of 6 reported families and interestingly, affected members of one of these families also exhibit congenital glaucoma with variable expressivity. In this study we report on a large Filipino family with characteristic skull lesions and juvenile onset open angle glaucoma (JOAG).

Methods : Eighteen members of a 4-generation family were recruited. All subjects underwent a comprehensive eye exam and skull radiography, and DNA samples were obtained. Whole exome sequencing (WES) was performed in 5 family members with JOAG. An in-house WES pipeline was used to align sequence reads and complete variant calling and annotation. After confirming the absence of mutations in genes known to cause early-onset glaucoma WES data was filtered to retain rare variants (minor allele frequency <1%) that were protein altering and predicted to be pathogenic. Sanger sequencing was done to confirm segregation of candidate variants.

Results : Six family members were diagnosed with JOAG and presented with a mean age at diagnosis of 25.5 years, 83% blind in at least one eye, mean intraocular pressure of 29.4 mmHg, and glaucomatous optic nerves. No mutations were found in known disease-causing genes and after variant filtering, a known recurrent heterozygous stop gain mutation, SGMS2 c.148C>T(p.Arg50*), was identified in all subjects with JOAG. Ten family members had abnormal skull radiographs, including all 6 JOAG subjects. The SGMS2 p.Arg50* variant was present in all family members with skull abnormalities.

Conclusions : Here we report on the first Filipino family with CDL and confirm segregation of a recurrent SGMS2 variant found in other families with European Caucasian ancestry. Our study also identifies a second CDL family with early-onset glaucoma raising the possibility that SGMS2 genetic variation can contribute to glaucoma pathogenesis. SGMS2 impacts metabolism of ceramide, sphingomyelin and diacyglycerol, all of which could contribute to trabecular meshwork dysfunction and/or retinal ganglion cell degeneration in glaucoma. Further work is needed to confirm a role for SGMS2 in glaucoma development.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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