Frontiers in Genetics (Sep 2021)

ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

  • Carlos Alberto González-Domínguez,
  • Carlos Alberto González-Domínguez,
  • Moisés O. Fiesco-Roa,
  • Moisés O. Fiesco-Roa,
  • Samuel Gómez-Carmona,
  • Anke Paula Ingrid Kleinert-Altamirano,
  • Anke Paula Ingrid Kleinert-Altamirano,
  • Miao He,
  • Earnest James Paul Daniel,
  • Kimiyo M. Raymond,
  • Melania Abreu-González,
  • Sandra Manrique-Hernández,
  • Sandra Manrique-Hernández,
  • Ana González-Jaimes,
  • Roberta Salinas-Marín,
  • Carolina Molina-Garay,
  • Karol Carrillo-Sánchez,
  • Luis Leonardo Flores-Lagunes,
  • Marco Jiménez-Olivares,
  • Anallely Muñoz-Rivas,
  • Mario E. Cruz-Muñoz,
  • Matilde Ruíz-García,
  • Hudson H. Freeze,
  • Héctor M. Mora-Montes,
  • Carmen Alaez-Verson,
  • Iván Martínez-Duncker,
  • Iván Martínez-Duncker

DOI
https://doi.org/10.3389/fgene.2021.744884
Journal volume & issue
Vol. 12

Abstract

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This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1, the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N-glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient’s serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.

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