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. 2023 Jan;11(1):e2064.
doi: 10.1002/mgg3.2064. Epub 2022 Sep 23.

A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro-Caribbean individual

Mary Maj  1 , Christie L Taylor  2 , Kevin Landau  1 , Helga V Toriello  3 , Dong Li  4   5   6 , Elizabeth J Bhoj  4   5   6 , Hakon Hakonarson  3   4   6 , Beverly Nelson  7   8 , Sarah Gluschitz  9 , Ruth H Walker  10   11 , Andrew K Sobering  1   12   13
Affiliations

A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro-Caribbean individual

Mary Maj et al. Mol Genet Genomic Med. 2023 Jan.

Abstract

Background: SYNJ1 encodes Synaptojanin-1, a dual-function poly-phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy.

Methods: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant.

Results: We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years.

Conclusions: We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1-related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

Keywords: SYNJ1; developmental and epileptic encephalopathy; synaptojanin 1.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
A 14‐year‐old individual affected with SYNJ1‐related developmental epileptic encephalopathy. Severe generalized dystonia, muscle atrophy, contractures, scoliosis, apparent hypertelorism, and risus sardonicus are evident
FIGURE 2
FIGURE 2
Protein domains of SYNJ1 and its known variants. Pathogenic variants associated with SYNJ1‐related developmental and epileptic encephalopathy are on the left. Variants associated with SYNJ1‐related parkinsonism are on the right. The predicted truncating variants annotated with boxes are found in individuals who have parkinsonism but with compound heterozygosity for a missense variant in SYNJ1. The Sac1 phosphatase domain is in green, the catalytic 5′PP domain is in orange, and the proline‐rich domain is in purple
See this image and copyright information in PMC

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