Response to van Riel et al

Published:November 16, 2022DOI:
      Long before the availability of genomic sequencing technologies, initial descriptions of Mendelian disorders relied on clinical observation of individual patients and families. Medical dysmorphology and detailed pedigrees provided evidence for inheritance patterns while occasionally allowing a glimpse of variable expressivity and the milder end of the phenotypic spectrum for some disorders. Most well-established genetic syndromes were first discovered clinically in patients with classic manifestations and later matched to pathogenic variants in previously unknown genes. Separately, more genotyping and genomic sequencing of large cohorts have revealed associations between pathogenic variants and more common disorders, such as the dozens of pathogenic copy number variants that broadly correlate with an array of medical and neurodevelopmental diagnoses.
      • Martin C.L.
      • Wain K.E.
      • Oetjens M.T.
      • et al.
      Identification of neuropsychiatric copy number variants in a health care system population.
      For both categories—well known, clinically defined Mendelian syndromes and newer, poorly phenotyped pathogenic variants identified via clinical cohorts—important questions remain about population prevalence, clinical penetrance, phenotypic spectrum, and disease risk. The recent availability of large-scale data sets from multiple biobanks, including Geisinger’s MyCode, the UK Biobank, and other genome-first population-based initiatives, has begun to reveal surprising differences from historically estimated disease prevalence and penetrance outside of medically ascertained patients and families.
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