PIGF deficiency causes a phenotype overlapping with DOORS syndrome

Smrithi Salian; Hind Benkerroum; Thi Tuyet Mai Nguyen; Sheela Nampoothiri; Taroh Kinoshita; Têmis Maria Félix; Fiona Stewart; Sanjay M Sisodiya; Yoshiko Murakami; Philippe M Campeau

doi:10.1007/s00439-020-02251-2

PIGF deficiency causes a phenotype overlapping with DOORS syndrome

Hum Genet. 2021 Jun;140(6):879-884. doi: 10.1007/s00439-020-02251-2. Epub 2021 Jan 2.

Affiliations

¹ Department of Pediatrics, CHU Sainte-Justine Research Center, University of Montreal, 3175, Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.
² Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre (AIMS), Kochi, 682041, India.
³ Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
⁴ Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
⁵ Northern Ireland Regional Genetics Centre, Belfast, BT97AB, Northern Ireland.
⁶ NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
⁷ Department of Pediatrics, CHU Sainte-Justine Research Center, University of Montreal, 3175, Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada. [email protected].

PMID: 33386993
DOI: 10.1007/s00439-020-02251-2

Abstract

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.

MeSH terms

Adolescent
Amino Acid Sequence
Animals
Consanguinity
Craniofacial Abnormalities / genetics*
Craniofacial Abnormalities / metabolism
Craniofacial Abnormalities / pathology
Exome Sequencing
Female
Gene Expression
Glycosylphosphatidylinositols / deficiency*
Glycosylphosphatidylinositols / genetics
Glycosylphosphatidylinositols / metabolism
HEK293 Cells
Hand Deformities, Congenital / genetics*
Hand Deformities, Congenital / metabolism
Hand Deformities, Congenital / pathology
Hearing Loss, Sensorineural / genetics*
Hearing Loss, Sensorineural / metabolism
Hearing Loss, Sensorineural / pathology
Homozygote
Humans
Infant
Intellectual Disability / genetics*
Intellectual Disability / metabolism
Intellectual Disability / pathology
Male
Membrane Proteins / deficiency
Membrane Proteins / genetics*
Mutation, Missense*
Nails, Malformed / genetics*
Nails, Malformed / metabolism
Nails, Malformed / pathology
Seizures / genetics*
Seizures / metabolism
Seizures / pathology
Sequence Alignment

Substances

Glycosylphosphatidylinositols
Membrane Proteins
PIGF protein, human

Supplementary concepts

Digitorenocerebral Syndrome
Glycosylphosphatidylinositol deficiency