A 4-month-old male infant presents to the emergency department with recurrent hypoglycemia, lactic acidosis, hyperuricemia, hypertriglyceridemia, and massive hepatomegaly with a characteristic doll-like face. Liver biopsy shows glycogen accumulation and steatosis. Enzymatic assay confirms deficiency of glucose-6-phosphatase. Gene sequencing reveals biallelic pathogenic variants in G6PC on chromosome 17q21.31. Both parents are phenotypically normal but carrier-tested as heterozygous. The pedigree shows affected males and females, transmission from unaffected parents, and no male-to-male transmission. The inheritance pattern marked **A** in the diagram is most consistent with which of the following?
A. Autosomal dominant inheritance with de novo mutations in the proband and unaffected parents
B. Autosomal recessive inheritance with biallelic G6PC mutations in the proband and heterozygous carrier status in both parents
C. Mitochondrial inheritance with maternal transmission and variable expression in offspring
D. X-linked recessive inheritance with hemizygous males affected and heterozygous carrier females
Explanation
Why option 1 is correct
Glycogen storage disease type I (GSD Ia) is caused by biallelic pathogenic variants in the G6PC gene located on chromosome 17q21.31, inherited in an autosomal recessive pattern. The clinical presentation—recurrent hypoglycemia, lactic acidosis, hepatomegaly, and failure to respond to glucagon—is pathognomonic for GSD Ia. Both parents are phenotypically normal obligate carriers (heterozygous for one mutant allele each), and the proband inherited one mutant allele from each parent. The pedigree demonstrates the hallmark features of autosomal recessive inheritance: affected individuals of both sexes, transmission from unaffected carrier parents, and absence of male-to-male transmission. The structure marked A—autosomal recessive inheritance—is the correct inheritance pattern for GSD Ia as confirmed by biallelic G6PC mutations.
Why each distractor is wrong
Option 2 (X-linked recessive): X-linked recessive inheritance would show affected males and carrier females, but critically would demonstrate male-to-male transmission being impossible (affected fathers cannot pass the X chromosome to sons). The pedigree shows both males and females affected without this pattern, and the proband's father is unaffected, ruling out X-linked inheritance. Additionally, G6PC is located on chromosome 17, not the X chromosome.
Option 3 (Autosomal dominant): Autosomal dominant inheritance typically shows vertical transmission across generations with affected individuals in every generation, and affected individuals usually have at least one affected parent. In this case, both parents are phenotypically normal, and the proband has biallelic mutations (not monoallelic), which is incompatible with dominant inheritance. De novo dominant mutations would present as monoallelic variants, not biallelic.
Option 4 (Mitochondrial): Mitochondrial inheritance is characterized by maternal-only transmission (affected mothers pass the condition to all offspring; affected fathers do not pass it to any offspring). The pedigree shows both parents contributing to the proband's disease (biallelic nuclear gene mutations), and the paternal uncle's affected daughter demonstrates paternal transmission, which excludes mitochondrial inheritance entirely.
High-YieldNEET PG
GSD Ia is autosomal recessive (G6PC on chromosome 17); both parents are obligate carriers; biallelic mutations cause disease; no male-to-male transmission pattern.
Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I. Genet Med. 2014;16(11):e1.
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