FIG. 1.

Phenomena contributing to phenotypic heterogeneity in monogenic disorders. Left and middle boxes. Squares represent individuals carrying the same variant in a gene. Left box. Shaded square means the individual manifests the disease phenotype. Non‐shaded square means the individual does not manifest the disease phenotype (non‐penetrance). Middle box. Shaded square means the individual manifests the disease phenotype with different degree of severity. Non‐penetrance (non‐shaded squares) can be viewed as an extreme endpoint of variable expressivity. Right box. Individual carrying a variant in a pleiotropic gene with multisystemic effects. In the example, a variant in the NKX2‐1 gene encoding the thyroid transcription factor 1, with involvement (shaded squares) of the nervous system (chorea, choreoathetosis), pituitary gland (cystic mass), thyroid (congenital hypothyroidism), lung (neonatal respiratory distress, chronic interstitial lung diseases), and urinary system (megabladder).