PTPN4 germline variants result in aberrant neurodevelopment and growth

Protein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we ide...

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Bibliographic Details
Published in:HGG advances 2021-07, Vol.2 (3), p.100033, Article 100033
Main Authors: Chmielewska, Joanna J., Burkardt, Deepika, Granadillo, Jorge Luis, Slaugh, Rachel, Morgan, Shamile, Rotenberg, Joshua, Keren, Boris, Mignot, Cyril, Escobar, Luis, Turnpenny, Peter, Zuteck, Melissa, Seaver, Laurie H., Ploski, Rafal, Dziembowska, Magdalena, Wynshaw-Boris, Anthony, Adegbola, Abidemi
Format: Article
Language:English
Subjects:
Developmental Delay
Intellectual Disability
Life Sciences
Macrocephaly
Neurodevelopment
Neurons and Cognition
Protein tyrosine phosphatase
PTPN4
Somatic growth anomaly
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Summary:Protein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans. Using exome and targeted sequencing, we identified six primarily de novo PTPN4 variants and report an associated phenotype that converges on neurodevelopment and growth. Conservation at variant loci combined with analysis of variant effect on protein trafficking and catalytic activity for selected variants establish a distinct PTPN4-related developmental disorder.
ISSN:2666-2477
2666-2477
DOI:10.1016/j.xhgg.2021.100033