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

Area of Science:

• Biochemistry
• Genetics
• Clinical Medicine

Background:

• Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic diseases affecting N-glycan synthesis.
• ALG1-CDG is caused by defects in ALG1, a key enzyme in the dolichol-phosphate pathway essential for N-glycan precursor formation.

Purpose of the Study:

• To report the first case of ALG1-congenital disorder of glycosylation (ALG1-CDG) in a patient from Latin America.
• To characterize the genetic basis and clinical presentation of ALG1-CDG in a Mexican mestizo patient with neurological involvement.

Main Methods:

• Clinical exome sequencing was performed to identify genetic variants.
• Analysis of serum transferrin profile and N-linked mannose-deprived tetrasaccharide marker was conducted.
• Functional impact of identified ALG1 variants was assessed through in silico analysis of splicing and protein effect.

Main Results:

• A Mexican mestizo patient presented with a multi-systemic syndrome, including neurological deficits and a type I serum transferrin profile.
• Clinical exome sequencing identified complex alleles in the ALG1 gene: c.[208 + 16_208 + 19dup; 208 + 25G > T] and c.[208 + 16_208 + 19dup; 1312C > T].
• The patient's diagnosis of ALG1-CDG was confirmed by the presence of the pathognomonic N-linked mannose-deprived tetrasaccharide marker.

Conclusions:

• This study reports the first identified case of ALG1-CDG in Latin America, highlighting the genetic heterogeneity of the disorder.
• The identified complex ALG1 alleles, including a novel variant affecting alternative splicing, contribute to the pathogenic mechanism of ALG1-CDG.
• This case underscores the importance of genetic testing in diagnosing multi-systemic disorders with neurological involvement and expanding the geographic representation of rare diseases.