The oculocutaneous albinism cohort had 18 distinct mutations: nine in
TYR, five in
OCA2, two in
SLC45A2, and two in
SLC24A5. One subject, JC_10797, had two different mutations in the
SLC45A2 gene that have not been reported previously to our knowledge (
SLC45A2 c.443G>A, p.Gly148Asp;
SLC45A2 c.665C>A, p.Ser222Tyr). Neither of these variants appear in the gnomAD data (provided in the public domain by
gnomad.broadinstitute.org) of over 123,000 exomes and 15,000 genomes (accessed February 28, 2018). The significance of these mutations was also assessed using SIFT, PolyPhen-2, and PROVEAN analysis tools, as previously described.
16 The p.Gly148Asp mutation in
SLC45A2 received the following scores: SIFT, 0; PolyPhen-2, 1.000; and PROVEAN, −6.399, which are classified as damaging, probably damaging, and deleterious, respectively. The p.Ser222Tyr mutation in
SLC45A2 received the following scores: SIFT, 0.19; PolyPhen-2, 0.967; and PROVEAN, −2.142, which are classified as tolerated, probably damaging, and neutral, respectively. Although statistical analysis does not invariably support pathogenicity of the second mutation, it lies between two previously reported mutations within transmembrane domain 6 of the translated MATP protein (
SLC45A2 p.Phe221del
45 and
SLC45A2 p.Cys229Tyr
46). Thus, it is possible that it represents a hypomorphic polymorphism that, when existing in a compound heterozygous state with a pathogenic mutation, permits a pathogenic phenotype. Additionally, subject JC_11430 had a 10-base pair deletion that induces a frameshift leading to a premature stop codon (
TYR c.1422_1431del, p.Ile474IlefrTer8). This specific mutation has not been reported previously to our knowledge, but it overlaps with a known 11-base pair deletion (
TYR c.1423_1433del).
12 This subject also possessed a novel mutation in the
SCL24A5 gene (c.910A>G, p.Lys304Glu), which received the following scores: SIFT, 0.46; PlyPhen-2, 0.546; and PROVEAN, −0.831 (tolerated, possibly damaging, and neutral, respectively). Based on these statistical predictions and the heterozygous state of the mutation, we do not believe this to be a primary contributor to this subject's phenotype. All other mutations in the albinism cohort have been reported previously.