A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability

Abstract

Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society.