Heritability of Long‐Term Complications in Classic Galactosemia

ABSTRACT As a group, patients with classic galactosemia (CG) demonstrate a high prevalence of long‐term complications despite early detection and life‐long dietary restriction of galactose, which is the current standard of care. Individual outcomes, however, vary widely. For decades, research teams have sought to identify potential environmental, metabolic, and/or galactose‐1‐phosphate uridylyltransferase ( GALT ) allelic differences that might explain this variability—with limited success. Among large cohorts, only severe brain‐related disease in infancy has been associated with increased prevalence of complications, and only the presence of predicted or detected residual GALT activity has been associated with decreased prevalence. While significant, these factors fail to account for the majority of long‐term outcome variability in CG. Here, we tested whether genetic factors, both inside and outside the GALT locus, might contribute to variability in speech/voice/language, cognitive, and/or motor outcomes among patients. Specifically, we compared outcomes among 66 sets of affected siblings who share both GALT genotype and genetic background, 54 unrelated CG patients who share GALT genotype (p.Gln188Arg/p.Gln188Arg) but not genetic background, and 52 unrelated CG patients who share neither GALT genotype nor genetic background. Heritability estimates for all three complications demonstrate substantial genetic contributions, with point estimates of 100% heritability for all three. Less than 8% of this heritability appears due to residual GALT activity from hypomorphic GALT alleles. Combined with prior data demonstrating clustering of all three outcomes, these results offer compelling evidence for the existence of genetic modifiers of developmental outcomes in CG beyond the GALT locus.