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Eur J Med Genet. 2019 Apr 29. pii: S1769-7212(19)30178-8. doi: 10.1016/j.ejmg.2019.04.017. [Epub ahead of print]

PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.

Author information

1
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: katrin.ounap@kliinikum.ee.
2
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
3
Children's Clinic, Tartu University Hospital, Tartu, Estonia; Department of Paediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
4
Radiology Clinic of Tartu University Hospital, Tartu, Estonia; Department of Radiology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
5
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Yale University School of Medicine, Department of Genetics, New Haven, CT, USA.
6
Eye Clinic, Tartu University Hospital, Tartu, Estonia.
7
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Abstract

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

KEYWORDS:

Epileptic encephalopathy; PEHO syndrome; ZNHIT3 gene

PMID:
31048081
DOI:
10.1016/j.ejmg.2019.04.017

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