A 28-year-old Indian man presents to the fertility clinic with primary infertility. His wife has been unable to conceive after 3 years of unprotected intercourse. Semen analysis reveals azoospermia. His father had a similar history of infertility and fathered him via assisted reproductive technology (ART). The pedigree shows that his paternal grandfather was also infertile, and this trait has affected only males in the paternal lineage for three generations with no skipped generations. The structure marked **A** in the pedigree diagram represents the inheritance pattern observed in this family. Y-microdeletion analysis confirms a deletion in the AZFc region. Which of the following best describes the inheritance pattern and its key feature marked **A**?

Explanation

## Why Y-linked (holandric) inheritance — father-to-son transmission only is right The pedigree demonstrates the hallmark feature of Y-linked inheritance marked as **A**: transmission exclusively from father to son with no female involvement. The patient inherited the AZFc microdeletion from his father, who inherited it from his paternal grandfather. In Y-linked inheritance, every son of an affected father is affected, and no daughters can be affected or carriers because daughters inherit the X chromosome from their father, not the Y. This pattern matches the three-generation male-only lineage described. AZFc deletions on the Y chromosome are the most common Y-linked cause of non-obstructive azoospermia in Indian and global populations (Harrison 21e Ch 460; Nelson Pediatrics 21e Ch 99). ## Why each distractor is wrong - **Autosomal recessive inheritance**: Autosomal recessive conditions can affect both males and females equally and typically show affected individuals with unaffected carrier parents. This pedigree shows only males affected across generations with direct father-to-son transmission, not the typical autosomal recessive pattern of two unaffected carrier parents. - **X-linked recessive inheritance**: X-linked recessive traits show affected males transmitting the trait to all carrier daughters (who have affected sons). Affected fathers do NOT pass X-linked traits to sons; sons receive the Y from their father. This pedigree shows direct father-to-son transmission, which is incompatible with X-linkage. - **Mitochondrial inheritance**: Mitochondrial inheritance affects all children of affected mothers regardless of sex, and affected fathers do not transmit the trait to any offspring. This pedigree shows paternal transmission to sons only, which rules out mitochondrial inheritance. **High-Yield:** Y-linked (holandric) inheritance = father-to-son ONLY, all sons affected, NO daughters affected or carriers, NO skipped generations in males. AZFc microdeletions are the most common Y-linked cause of male infertility. [cite: Harrison 21e Ch 460; Nelson Pediatrics 21e Ch 99]