Genetic etiology dominated Down syndrome research, with trisomy 21 established as the principal cause through large cytogenetic series and parental data informing counseling and prenatal risk assessment. The period also foregrounded mosaicism and translocations as alternative etiologies, linking phenotypic variability to chromosomal origin and refining prognosis. Concurrent epidemiologic inquiries began to illuminate cancer risks and familial patterns, laying groundwork for integrated Down syndrome biology and surveillance.