The Liberfarb syndrome, a multisystem disorder including early-onset retinal degeneration, is caused by a founder mutation in the PISD gene in patients from Portugal, Brazil, and the Azores islands

Abstract

Purpose : We observed four individuals in two unrelated consanguineous families from Portugal and Brazil displaying recessively-inherited early-onset retinal degeneration (EORD), sensorineural hearing loss, microcephaly, intellectual disability and skeletal dysplasia with scoliosis and short stature. The phenotype matched that of a now deceased Azorean individual residing in the USA, described in 1986 in a case report. The purpose of this work was to identify the genetic mutation(s) leading to this condition, which we termed Liberfarb syndrome in honor of the author who first described it.

Methods : Standard and thorough clinical examination of patients (incl. ophthalmological, audiological, radiological and developmental assessment). Whole exome sequencing, direct Sanger sequencing. Minigene constructs for the splicing assay.

Results : Our patients shared a 3.16 MB region of autozygosity on chromosome 22q12.2 and were homozygous for a 10-bp deletion just upstream of the last exon of the PISD gene, lying in this interval. Sequencing of the PISD gene from surgical tissue from the original case described in 1986 revealed the identical 10-bp deletion. In transfected HEK cells, this variant led to the aberrant splicing of PISD primary transcripts and retention of the last intron. In vivo, this event presumably results in little PISD mRNA and to reduced function of the encoded phosphatidylserine decarboxylase enzyme, which converts phosphatidylserine to phosphatidylethanolamine.

Conclusions : We have identified the genetic etiology of Liberfarb syndrome, a condition characterized by EORD associated with skeletal, neurologic, and audiological features. Interestingly, other defects in the phospholipid synthesis pathway have been associated with similar phenotypes: spondylometaphyseal dysplasia with cone-rod dystrophy (PCYT1A gene), and Lenz-Majewski syndrome (sclerosing bone dysplasia, intellectual disability and multiple anomalies including hypoacusis; PTDSS1 gene). Our work documents the migration of a rare Portuguese founder mutation across two continents, highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, and raises the possibility of therapeutic phospholipid replacement.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.