A 35-year-old man presents with a painless left neck mass and pulsatile tinnitus. Imaging reveals a carotid body paraganglioma. His father had a similar tumor at age 40, but his mother is unaffected despite carrying the same SDHD mutation. The inheritance pattern shown in the pedigree is marked as **A** — paternal-only transmission with maternal imprinting. Which of the following best explains why this patient's mother, though a carrier of the SDHD mutation, remains clinically unaffected?

Explanation

## Why option 1 is right SDHD (PGL1) exhibits **maternal imprinting**, meaning the maternal allele is epigenetically silenced in paraganglioma-relevant tissues (carotid body, jugulotympanic, vagal paraganglia). Only the paternal allele is expressed. When the mother inherited the SDHD mutation from her parent, that mutation is on her maternal chromosome 11 — but because it is imprinted (silenced), it produces no protein and causes no disease. Her paternal SDHD allele (inherited from her father) remains wild-type and functional, rescuing the phenotype. This is the hallmark of parent-of-origin effects in SDHD-PGL1: disease occurs ONLY when the mutation is inherited from the father (the active paternal copy is now mutant); mutations inherited from the mother cause no disease in the carrier. The patient inherited the mutation from his father, so it is on his active paternal allele, causing disease. ## Why each distractor is wrong - **Option 2**: SDHD is located on chromosome 11q23 (autosomal), not the X chromosome. X-inactivation is irrelevant to SDHD inheritance. This confuses SDHD with X-linked conditions and is factually incorrect. - **Option 3**: SDHD mutations do not require homozygosity to manifest; they are dominant. Heterozygous carriers with a paternal mutation are fully affected. The mother's unaffected status is not due to heterozygosity protection but to imprinting of her maternal allele. - **Option 4**: Spontaneous reversion during meiosis is not a recognized mechanism for SDHD and does not explain the consistent parent-of-origin pattern. Imprinting, not mutation reversion, explains why the mother's mutation is silent. **High-Yield:** SDHD (PGL1) = paternal-only disease transmission due to maternal imprinting; mothers who carry the mutation are unaffected but can transmit it to their children, who will be at risk if they inherit it from their father. [cite: Lenders et al. Endocrine Society Pheochromocytoma/Paraganglioma Guidelines 2014; Hensen & Bayley Genetics 2011 (Imprinting in SDHD); Thompson & Thompson 8th ed.]