The global population genetics of GPNMB-associated amyloidosis cutis dyschromica: ancestry-specific variation and likely underdiagnosis

Abstract Amyloidosis cutis dyschromica (ACD) is a rare recessive pigmentary disorder caused by biallelic loss-of-function (LoF) variants in GPNMB . Almost all reported patients are East or Southeast Asian, and it is unknown whether this reflects allele distribution or ascertainment. Using gnomAD v4.1, I identified 114 high-confidence predicted LoF (pLoF) variants on the MANE Select transcript and estimated carrier frequencies and expected biallelic prevalence across ancestry groups. Carrier frequencies were highest in Ashkenazi Jewish (1 in 251) and East Asian (1 in 261) individuals, followed by non-Finnish Europeans (1 in 358) and Admixed Americans (1 in 422). Under Hardy–Weinberg proportions, about 183 people in Mexico (95% interval 141–344) and about 40 Ashkenazi Jews worldwide (25–68) are expected to carry biallelic pLoF alleles. A literature audit found no reported ACD cases of Latin American or Ashkenazi Jewish origin, against at least 100 reported patients worldwide. The Ashkenazi burden is driven by a single founder splice-donor allele, c.367+2T>C (57 of 80 gnomAD copies). In Admixed Americans, 70% of pLoF alleles are shared with Europeans and 30% come from four alleles essentially absent elsewhere. Heterozygous pLoF carriers in 394,841 UK Biobank exomes showed no association across 4,529 traits, consistent with recessive inheritance. Variants that disrupt the essential MITF binding site of the GPNMB proximal promoter (MCS3) were rare, but one, 7-23246653-A-T, is confined to African and Admixed American chromosomes and is a candidate for functional testing. These results indicate that ACD is likely underdiagnosed in Latin America and among Ashkenazi Jews, and that GPNMB belongs on diagnostic panels for pigmentary disorders beyond East Asia.