Molecular Findings in Families with an Initial Diagnose of Autosomal Dominant Retinitis Pigmentosa (adRP)

Abstract

Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP. Exceptions to the proposed mode of inheritance were extracted from our comprehensive patient and family database. In a subset of 300 well-characterized families with a probable diagnosis of adRP, 195 (70%) have dominant mutations in known adRP genes but 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive disease. It is currently possible to determine the underlying disease-causing gene and mutation in approximately 80% of families with an initial diagnosis of adRP, but 10% of "adRP" families have a variant mode of inheritance. Informed genetic diagnosis requires close collaboration between clinicians, genetic counselors, and laboratory scientists.

Keywords: Autosomal dominant retinitis pigmentosa; Linkage mapping; Next-generation sequencing; Prevalence of mutations; Retinitis pigmentosa (RP); Semidominant inheritance; X-linked retinitis pigmentosa.

Fig.29.1

Pedigree of a family with a clinical diagnosis of RP and apparent autosomal dominant inheritance. The disease-causing mutation in the family is a 1 bp deletion in ORF15 of the X-linked RPGR gene (Mears et al. 2000)

Fig.29.2

Pedigree and segregating haplotypes in a family with adRP caused by a Glu847Lys missense mutation in HK1 (Sullivan et al. 2014). Black bars show the shared haplotype segregating with the HK1 mutation on chromosome 10q22.1, and gray bars represent the unrelated haplotypes in trans. Individual 16 carries two copies of the mutation-associated haplotype but with different recombinant end points

Fig.29.3

Pedigree of a nuclear family within a larger family with adRP caused by an RP1 Arg677X mutation (Sullivan et al. 1999). Parents 04 and 05 are related and both are heterozygous for the RP1 mutation. Individuals 07–09 inherited one copy of the mutation, and individuals 06 and 11 inherited two copies. Photograph below is a restriction digest showing segregation of the wild-type (lower band) and mutant (upper band) RP1 alleles of the individuals in the pedigree

Fig.29.4

Pedigree of a family with a provisional diagnosis of adRP but an apparent non-penetrant individual, 2.2 (Wheaton et al. 2016). Molecular testing showed an autosomal dominant RP1 Arg677X mutation segregating in individuals 2.3, 3.4, and 3.5, whereas individual 3.3 is a compound heterozygote for USH2A [Cys419Phe];[Glu767Serfs*21] mutations. Individual 2.2 is a carrier of the USH2A Cys419Phe mutation but does not carry the RP1 mutation