Non-functional alternative splicing caused by a Latino pathogenic variant in a case of PMM2-CDG

González-Domínguez, Carlos; Villarroel, Camilo E.; Rodríguez-Morales, M.; Manrique-Hernández, S.; González-Jaimes, Ana; Rodríguez-Morales, Miguel; Beutelspacher, K.; Molina-Garay, Carolina; Carrillo‐Sánchez, Karol; Flores-Lagunes, Luis Leonardo; Jiménez-Olivares, M.; Muñoz-Rivas, Anallely; Cruz-Muñoz, Mario Ernesto; Mora-Montes, Héctor M.; Salinas-Marín, Roberta; Aláez-Verson, Carmen; Martínez-Duncker, Iván

doi:10.1016/j.ymgmr.2021.100781

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…In most disease-related genes, variants affecting splicing are not fully characterized because variant screening is restricted to gDNA. In our experience involving ATP6V0A2-CDG and more recently PMM2-CDG, amplification of cDNA transcripts is an invaluable tool to demonstrate non-functional alternative splicing, identifying the consequence on the protein and establishing the pathogenicity mechanism ( Bahena-Bahena et al, 2014 ; González-Domínguez et al, 2020 , 2021 ). Of the six reported disease-causing mutations in HGMD that potentially affect splicing of ALG1 , only one has been experimentally confirmed ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…[18] These uncharted mutations, especially 1 corresponding to a coding stop, are significant as they likely lead to premature termination and a truncated, possibly nonfunctional protein. [19,20] Each mutation, independently, may disrupt the function of the ABCC2 gene. However, when presented together, their combined effect could be magnified, potentially leading to an intensified clinical presentation.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and follow-up of a newborn with Dubin–Johnson Syndrome: A clinical case report

Zhang,

Zuo,

Gao

2024

Medicine

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Background: Dubin–Johnson syndrome (DJS) is a rare autosomal recessive liver disorder, characterized by conjugated hyperbilirubinemia. This case report investigates the clinical characteristics and longitudinal outcomes of a neonate diagnosed with DJS. Methods: A newborn presented with elevated bilirubin levels and abnormal liver enzyme readings. Comprehensive genetic evaluation was conducted, which included peripheral blood sample collection from the infant and both parents after obtaining informed consent and high-throughput trio exome sequencing was performed. The genetic analysis revealed 2 significant mutations in the ABCC2 gene on chromosome 10: the insertion mutation c.4237(exon30)_c.4238(exon30)ins CT, inherited from the father, and the missense mutation c.517(exon5)G > A, inherited from the mother. Both mutations were classified as pathogenic according to the ACMG 2015 guidelines, indicating a compound heterozygous inheritance pattern. The patient’s treatment regimen included phototherapy, which was initiated to address her jaundice upon admission. To support liver function and regulate gut activity, oral ursodeoxycholic acid (20 mg/kg/dose, twice a day) and probiotics were administered. Additionally, a postdischarge medication plan involving a low-dose regimen of phenobarbital (3.5 mg/kg/dose, twice a day) was implemented for 2 weeks. Results: During a 2-year follow-up after discharge, the infant’s bilirubin levels significantly decreased, and liver enzymes, including GGT, progressively normalized. Conclusion: This case report enhances the understanding of DJS in neonates by emphasizing the clinical ramifications of compound heterozygous mutations within the ABCC2 gene and documenting the evolution of the disease. The gradual normalization of liver function tests suggests potential compensatory mechanisms in response to the genetic abnormalities in neonates with DJS. The correlation between the patient’s genetic profile of compound heterozygosity and her milder clinical phenotype warrants attention, suggesting that this specific genetic configuration may be associated with less severe manifestations of the disease. The necessity for long-term follow-up is highlighted, recognizing that intercurrent stress conditions could influence the hepatic profile and potentially exacerbate symptoms. Such sustained observation is crucial to further delineate the genomic and clinical landscape of DJS, offering opportunities to refine prognostic and therapeutic approaches.

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Non-functional alternative splicing caused by a Latino pathogenic variant in a case of PMM2-CDG

Cited by 2 publications

References 30 publications

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

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

Clinical characteristics and follow-up of a newborn with Dubin–Johnson Syndrome: A clinical case report

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