PISD

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: Franklin by Genoox

Four individuals in two unrelated but consanguineous families affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia underwent DNA examination which revealed that all f ourpatients were homozygous for a single variant inPISD, within a shared haplotype, likely due to the presence of a common ancestor for all of them approximately five generations ago.

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0030045

Submitter: ClinGen

The *PISD* gene is located on chromosome 22 at 22q12.2 and encodes phophatidylserine decarboxylase, which catalyzes the conversion of phosphatidylserine (PS) to phosphatidylethanolamine (PE) in mitochondria. *PISD* was first reported in relation to autosomal recessive Liberfarb syndrome in 2019 (Peter et al., PMID 31263216). Phenotypes of the syndrome include short stature and skeletal anomalies, and may also include joint laxity, retinal degeneration, hearing loss, microcephaly, developmental delay and intellectual disability. Six variants (4 missense and 2 splicing) have been reported in seven probands from four publications (PMIDs: 31263216, 30858161, 30488656, 38801004) and are included in this curation. The mechanism of pathogenicity is reported to be loss of function (PMID 31263216). This gene-disease relationship is also supported by experimental evidence (biochemical, functional alteration and model organisms) (PMIDs: 30858161, 30488656, 23250747, 22433850, 16192276, 31285171, 20702701). Other mitochondrial genes *(LONP1, PYCR1, GPX4, AIFM1* and *HSPA9*) have been implicated in conditions with similar phenotypes including skeletal abnormalities, cataracts, mitochondrial dysfunction, hearing loss and developmental delay. Patient fibroblasts demonstrated impaired PISD activity, mitochondrial dysfunction and abnormal mitochondrial morphology that could be rescued with PE supplementation or genetic complementation (PMID 30858161). Pisd knockdown in CHO cells, deletion of Psd1 in yeast, a Pisd knockout mouse model and Pisd knockdown in mouse skeletal muscle demonstrated similarities in cellular phenotypes to patient fibroblasts (PMIDs: 23250747, 22433850, 16192276, 31285171). Additionally, knockdown of *Psd* in the *Drosophila* eye showed light-dependent retinal degeneration (PMID 20702701). The observation that mice without Pisd function die early in embryonic development and that no reported human cases have been homozygous or compound heterozygous for loss-of-function variants suggests that complete loss of PISD function may be embryonically lethal in humans as well. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 2nd, 2024 (SOP Version 11).