期刊
GENETICS IN MEDICINE
卷 21, 期 12, 页码 2734-2743出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-019-0595-x
关键词
PISD; Liberfarb syndrome; skeletal dysplasia; retinal degeneration; phospholipid metabolism
资金
- Swiss National Science Foundation [176097]
- Jurg Tschopp MD-PhD Scholarship
- PhD Fellowship in Life Sciences (Faculty of Biology and Medicine, University of Lausanne)
- Fondation Guillaume Gentil
- National Institutes of Health (NIH) [U53HD090255]
- Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18kk020500]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP17H01539, JP16H05357]
Purpose: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. Methods: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. Results: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3: c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. Conclusion: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.
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