July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
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
Author Affiliations & Notes
  • Virginie Gisèle Peter
    Department. of Computational Biology, University of Lausanne, Lausanne, Switzerland
  • Mathieu Quinodoz
    Department. of Computational Biology, University of Lausanne, Lausanne, Switzerland
  • Jorge Pinto-Basto
    CGC Genetics, Porto, Portugal
  • Sergio De Sousa
    Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
    University Clinic of Genetics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
  • Silvio Alessandro Di Gioia
    Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, United States
  • Gabriela Soares
    Center for Medical Genetics Dr. Jacinto Magalhães, Porto Hospital Center, Porto, Portugal
  • Gabriela Ferraz Leal
    Fernando Figueira Integral Medicine Institute, Recife, Brazil
  • Eduardo Silva
    Centro Cirúrgico de Coimbra, Coimbra, Portugal
  • Elizabeth Engle
    Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, United States
    Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
  • Noriko Miyake
    Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  • Naomichi Matsumoto
    Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  • Sheila Unger
    Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
  • Frederic Shapiro
    Department of Medicine/Endocrinology, Stanford University School of Medicine, Palo Alto, California, United States
  • Belinda Campos-Xavier
    Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
  • Andrea Superti-Furga
    Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
  • Carlo Rivolta
    Department. of Computational Biology, University of Lausanne, Lausanne, Switzerland
    Dept. of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
  • Footnotes
    Commercial Relationships   Virginie Peter, None; Mathieu Quinodoz, None; Jorge Pinto-Basto, None; Sergio De Sousa, None; Silvio Alessandro Di Gioia, None; Gabriela Soares, None; Gabriela Ferraz Leal, None; Eduardo Silva, None; Elizabeth Engle, None; Noriko Miyake, None; Naomichi Matsumoto, None; Sheila Unger, None; Frederic Shapiro, None; Belinda Campos-Xavier, None; Andrea Superti-Furga, None; Carlo Rivolta, None
  • Footnotes
    Support  The Swiss National Science Foundation (176097); The Doctoral School of FBM, University of Lausanne
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 411. doi:
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      Virginie Gisèle Peter, Mathieu Quinodoz, Jorge Pinto-Basto, Sergio De Sousa, Silvio Alessandro Di Gioia, Gabriela Soares, Gabriela Ferraz Leal, Eduardo Silva, Elizabeth Engle, Noriko Miyake, Naomichi Matsumoto, Sheila Unger, Frederic Shapiro, Belinda Campos-Xavier, Andrea Superti-Furga, Carlo Rivolta; 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. Invest. Ophthalmol. Vis. Sci. 2019;60(9):411.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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