In 3 patients with Zellweger syndrome (PBD1A; 214100), including a severely affected patient who was studied by Gartner et al. (1992) (patient PBD002) and another patient in whom Reuber et al. (1997) had identified a PEX1 splice donor mutation, Collins and Gould (1999) identified homozygosity or compound heterozygosity for a 1-bp insertion (c.2097insT) in exon 13 of the PEX1 gene. Screening for 2097insT in 32 additional CG1 patients revealed that 3 were homozygous and 12 heterozygous for the insertion. The authors concluded that 2097insT is a common allele in the CG1 patient population, and noted that in contrast to the other common mutation, G843D (602136.0001), which is associated with a trend toward the mild end of the ZS phenotypic spectrum, this second common PEX1 mutation is associated with severe phenotypes.
Steinberg et al. (2006) gave the allele frequency of this mutation as 0.35 in PEX1-deficient patients.
In a brother and sister with Heimler syndrome-1 (HMLR1; 234580), originally reported by Heimler et al. (1991), Ratbi et al. (2015) identified compound heterozygosity for the c.2097dupT mutation (c.2097dupT, NM_000466.2) in the PEX1 gene and a c.2114T-G transversion, resulting in a leu705-to-trp (L705W; 602136.0006) substitution. In an unrelated 24-year-old woman with HMLR1, they identified compound heterozygosity for the 2097dupT mutation and a c.1742G-C transversion, resulting in an arg581-to-pro (R581P; 602136.0007) substitution. The mutations segregated with disease in both families, and were not found in 770 in-house exomes; in addition, the L705W mutation was not found in public databases, whereas the R581P mutation was present in 1 of 121,398 alleles in the ExAC Browser (minor allele frequency less than 0.000033). The 3 affected individuals all had sensorineural hearing loss, enamel hypoplasia, and nail defects, but did not exhibit dysmorphism or additional neurologic features. Complementation assays in transfected PEX1-null cells demonstrated that the c.2097dupT variant resulted in no complementation, whereas transfection with the c.1742G-C and c.2114T-G variants rescued peroxisomal biogenesis in 23% and 58% of cells, respectively.
