PNPLA6

Inheritance Pattern: AR

Disease ID:MONDO:0100155

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100155

Submitter: ClinGen

The PNPLA6 gene is located on chromosome 19 at 19p13.2 and encodes the patatin-like phospholipase domain-containing protein 6, which deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. PNPLA6 was first reported in relation to autosomal recessive retinal dystrophy-ataxia-pituitary hormone abnormalities-hypogonadism (RAPH) syndrome in 2014 (Synofzik et al., PMID: 24355708). The major features of this disorder include pituitary hormone abnormalities which involve growth hormone deficiency resulting in short stature, as well as hypothyroidism. Additional features reported in multiple patients include lower limb spasticity, distal muscle wasting, cerebellar atrophy, increased patellar reflexes, neuropathy, trichomegaly, alopecia, and mild cognitive impairment. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability in the following disease entities which ended up being lumped into one disease entity: Boucher-Neuhauser syndrome (OMIM:215470), Oliver-McFarlane syndrome (OMIM:275400), Laurence-Moon syndrome (OMIM:245800), and Gordon-Holmes syndrome (no OMIM entry, but Orphanet lists this as cerebellar ataxia hypogonadism syndrome (ORPHA:1173). The disorder listed in OMIM as spastic paraplegia 39, autosomal recessive (OMIM:612020) was split from the aforementioned lumped entity due to significant phenotypic variability and has been curated separately as PNPLA6-related spastic paraplegia with or without ataxia. Thirteen variants (eight missense, one essential splice site, three frameshift, and one tandem intragenic duplication of multiple exons) that have been reported in nine probands in three publications (Synofzik et al., 2014, PMID: 24355708; Topaloglu et al., 2014, PMID: 25033069; Hufnagel et el., 2015, PMID: 25480986) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is biallelic loss of function. This gene-disease relationship is also supported by a zebrafish knockdown animal model which has fewer motor axons as well as increased defects in axon branching and truncation, a feature that correlates with axonal neuropathy seen in some patients (Song et al., 2013, PMID: 22996643). In addition, several variants seen in patients were unable to rescue the zebrafish morphant phenotype (PMID: 25480986). In summary, PNPLA6 is definitively associated with autosomal recessive RAPH syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 11.02.2022 (SOP Version 9.0).

Inheritance Pattern: AR

Disease ID:MONDO:0100155

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100149

Submitter: ClinGen

The PNPLA6 gene is located on chromosome 19 at 19p13.2 and encodes the patatin-like phospholipase domain-containing protein 6, which deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. PNPLA6 was first reported in relation to PNPLA6-related spastic paraplegia with or without ataxia in 2008 (Rainier et al., PMID: 18313024). This disease is characterized by childhood to adult onset of progressive spasticity usually in the lower limbs, muscle weakness, peripheral neuropathy, increased reflexes, cerebellar atrophy, and ataxia. Cognitive impairment and growth hormone deficiency may also be present in some cases. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability in the following disease entities which ended up being lumped into one disease entity: Boucher-Neuhauser syndrome (OMIM:215470), Oliver-McFarlane syndrome (OMIM:275400), Laurence-Moon syndrome (OMIM:245800), and Gordon-Holmes syndrome (no OMIM entry, but Orphanet lists this as cerebellar ataxia hypogonadism syndrome (ORPHA:1173). The disorder listed in OMIM as spastic paraplegia 39, autosomal recessive (OMIM:612020) was split from the aforementioned lumped entity due to significant phenotypic variability and is curated here as PNPLA6-related spastic paraplegia with or without ataxia. Sixteen variants (13 missense, one nonsense, one frameshift, and one intragenic two-exon deletion) that have been reported in 11 probands in seven publications (PMID: 18313024; Yoon et al., 2013, PMID: 23733235; Synofzik et al., 2014, PMID: 24355708; Suchowersky et al., 2021, PMID: 34816117; Dong et al., 2021, PMID: 34256108; Emekli et al., 2021, PMID: 33210227; Nanetti et al., 2022, PMID: 35069422) are included in this curation. The mechanism of pathogenicity is reported to be loss of function based on various observations including reduced in-vitro enzymatic activity of recombinantly purified proteins containing patients’ variants, reduced enzymatic activity measured directly in patients’ fibroblasts, and the failure of proteins containing patients’ variants to rescue the phenotypes of zebrafish morphants as well as Drosophila null mutant animals. This gene-disease relationship is also supported by animal models (Akassoglou et al., 2004, PMID: 15051870; Kretzschmar et al., 1997, PMID: 9295388, Sunderhaus et al., 2019, PMID: 31780887). In particular, the mouse conditional brain specific knockout model showed abnormal flexion reflex as well as significantly poor motor coordination, whereas the Drosophila null model showed progressively severe reduction in locomotion. Additionally, non-genetic inhibition of PNPLA6 enzyme activity in humans through environmental exposure to certain toxic organophosphate compounds is well known to result in organophosphate compound-induced delayed neurotoxicity or OPIDN, a condition that resembles PNPLA6-related spastic paraplegia with or without ataxia that occurs due to biallelic genetic defects in this gene (Richardson et al., 2020, PMID: 32518884). In summary, PNPLA6 is definitively associated with autosomal recessive PNPLA6-related spastic paraplegia with or without ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 11.02.2022 (SOP Version 9.0).

Inheritance Pattern: AR

Disease ID:MONDO:0009514

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008980

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012787

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0010152

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012787

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012787

Submitter: PanelApp Australia