A 6-year-old boy presents with multiple café-au-lait macules (>5 mm), axillary freckling, and two cutaneous neurofibromas. His father is unaffected. Genetic testing confirms a heterozygous pathogenic variant in the NF1 gene on chromosome 17q11.2, marked as **B** in the pedigree diagram. Which of the following best describes the inheritance pattern and molecular consequence of this mutation?
A. Autosomal dominant inheritance with loss-of-function mutation causing RAS hyperactivation and tumorigenesis
B. X-linked dominant inheritance with skewed X-inactivation explaining variable phenotype in females
C. Autosomal recessive inheritance with haploinsufficiency leading to reduced neurofibromin expression
D. Mitochondrial inheritance with maternal transmission and heteroplasmy accounting for variable expressivity
Explanation
Why option 1 is correct
The structure marked B in the diagram represents the autosomal dominant NF1 gene on chromosome 17q11.2. The clinical presentation (café-au-lait macules, freckling, neurofibromas) combined with a de novo heterozygous pathogenic NF1 variant in an unaffected father confirms autosomal dominant inheritance with 100% penetrance by age 8. Loss-of-function mutations in NF1 eliminate neurofibromin, a Ras-GTPase activating protein (Ras-GAP), leading to uncontrolled RAS-MAPK signaling and tumorigenesis — this is the fundamental molecular mechanism driving NF1 pathogenesis. The 2021 Consensus Criteria recognize heterozygous NF1 variants as a standalone diagnostic criterion.
Why each distractor is wrong
Option 2: Autosomal recessive inheritance would require two mutated alleles; this patient has only one heterozygous variant. Haploinsufficiency does occur in NF1, but the inheritance pattern is dominant, not recessive.
Option 3: X-linked dominant inheritance would show a different pedigree pattern (affected males more severely affected, no male-to-male transmission). The NF1 gene is on chromosome 17, not the X chromosome. Skewed X-inactivation is not the mechanism in NF1.
Option 4: Mitochondrial inheritance shows maternal-only transmission and would not fit this pedigree (unaffected father with affected son is impossible in mitochondrial disease). Heteroplasmy is not relevant to nuclear gene mutations like NF1.
High-YieldNEET PG
NF1 is autosomal dominant with ~50% de novo mutations; loss of neurofibromin (a Ras-GAP) causes RAS hyperactivation — the key molecular switch in NF1 tumorigenesis.
