PREPL deficiency is an autosomal recessive disorder. Most often, both parents carry one allele with a mutation or deletion in PREPL, and the affected child inherits both abnormal alleles. Recurrence rate for a next child with the same parents is 25%. Deletions (both large and intragenic), nonsense mutations and point mutations in the PREPLgene have been found.
Apart from isolated PREPLdeficiency, PREPLis also involved in several recessive contiguous gene deletion syndromes: the 2p21 deletion syndrome, atypical hypotonia-cystinuria syndrome, hypotonia cystinuria syndrome and “atypical hypotonia-cystinuria syndrome without cystinuria”, caused by different combinations of nearby genes involved in the deletion. When SLC3A1, a gene next to PREPL, is involved in the deletion on both alleles, cystinuria is part of the phenotype and can help in the diagnosis by amino acid analysis of the urine.
Molecular diagnosis of PREPLdeficiency can be done by targeted sequencing of the PREPLgene or by analysis of a gene panel with next generation sequencing techniques. Whole exome sequencing and whole genome sequencing should also be able to identify PREPLmutations, depending on the accuracy of the interpretation. As deletions in the PREPL region relatively frequently contribute to PREPLdeficiency, it is important to include analysis of copy number variation in the 2p21 region in the diagnostic strategy.
It is important to note that not all array-CGH platforms are able to identify deletions in the PREPLregion, and when the diagnosis is strongly suspected, closer inspection of the resolution of the used array-CGH in the PREPLregion is advised.
As PREPLdeficiency has symptoms that resemble the Prader-Willi syndrome, it is useful to consider the possibility of PREPLdeficiency in patients with suspected Prader-Willi syndrome that could not be confirmed genetically.
PREPL(prolyl endopeptidase like) encodes a functional serine hydrolase but the substrates are still unknown. PREPL is involved in regulated secretion pathways and synaptic transmission, and deficiency of PREPLcauses a defect in neuromuscular transmission in infants. The precise pathophysiology of PREPLdeficiency is still incompletely understood.
A functional test was developed to detect PREPLactivity in lymphocytes derived from blood, to confirm pathogenicity of identified mutations.
PREPL