Neonatal cholestasis

Gene: LIPA

Green List (high evidence)

LIPA (lipase A, lysosomal acid type)
EnsemblGeneIds (GRCh38): ENSG00000107798
EnsemblGeneIds (GRCh37): ENSG00000107798
OMIM: 613497, Gene2Phenotype
LIPA is in 9 panels

2 reviews

Eleanor Williams (Genomics England Curator)

Comment when marking as ready: 3 unrelated cases with plausible disease causing mutations for Wolman disease which is neonatal onset and shows cholestasis phenotype.
Created: 25 Jul 2018, 2:08 p.m.
Comment on phenotypes: Added relevant phenotypes from Jane Hartley and from OMIM.
Created: 25 Jul 2018, 2:07 p.m.
Comment on publications: Added publications relating to cases.
Created: 25 Jul 2018, 2:05 p.m.
Comment on mode of inheritance: All reports are of homozygous or compound heterozgous mutations.
Created: 25 Jul 2018, 2 p.m.
Comment on list classification: More than 3 cases of variants in LIPA associated with Cholesteryl ester storage disease and 3 cases associated with the more severe neonatal onset Wolman disease so rating this gene as green.
Created: 25 Jul 2018, 1:59 p.m.
In OMIM LIPA is associated with Cholesteryl ester storage disease/Wolman disease. Cholestasis is listed as a common extrahepatic finding in patients with Cholesteryl ester storage disease by Bernstein et al 2013 (PMID: 23485521). Wolman disease (also known as lysosomal acid lipase deficiency) is a rare, neonatal-onset, fulminant subtype of CESD which may also manifest as neonatal cholestasis (Götze et al. (2015)(PMID: 26137452). OMIM reports findings by Aslanidis et al. (1996) (PMID: 8617513) who describe a CESD patient heterozygous for a variant in a splice donor site that results in a skipping of exon 8 and 97% of the mRNA originating from this allele. The other allele of the patient carried a premature termination mutation as well as a L179P mutation They also describe two siblings that are homozygous for a G-to-A mutation at position +1 of the splice donor site following exon 8 of the LIPA gene. Maslen and Illingworth (1993) (PMID: none) and Maslen et al. (1995) (PMID: 8598644) identified compound heterozygosity for this splice site mutation in the LIPA gene, inherited from their father, and the L179P mutation. The affected children were a sister and brother who presented with idiopathic hepatomegaly at ages 6 and 8 years, respectively. Muntoni et al. (1995)(PMID: 7759067) observed homozygosity for the splice site mutation (Klima et al., 1993)(PMID: 8254026) in a Spanish kindred with cholesterol ester storage disease. Exon 8 of the LIPA gene was deleted. A PubMed search finds Tinsa et al (2018)(PMID: 29702543) with a severe lysosomal acid lipase deficiency phenotype report an individual with a homozygous mutation in exon 3which interrupted the reading frame by a premature STOP codon and confirmed the diagnosis of Wolman disease. The parents were heterozygous for this mutation. Ikari et al 2018 (PMID: 29731497) report on two siblings with early onset lysosomal acid lipase deficiency or Wolman disease. Their parents had a consanguineous marriage. LIPA gene showed a single substitution within exon 3 which changed a tyrosine codon to a termination codon and lead to unstable mRNA and very low levels of enzyme activity.
Created: 25 Jul 2018, 1:47 p.m.

Jane Hartley (Birmingham Women and Children's Hospital)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
lysosomal acid lipase deficiency; cholestasis; cirrhosis; liver failure

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
  • Emory Genetics Laboratory
Phenotypes
  • Neonatal and Adult Cholestasis
  • lysosomal acid lipase deficiency
  • cholestasis
  • Cholesteryl ester storage disease 278000
  • Wolman disease 278000
OMIM
613497
Clinvar variants
Variants in LIPA
Penetrance
None
Publications
Panels with this gene

History Filter Activity

3 Sep 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

This panel has been subjected to extensive internal and external review.

25 Jul 2018, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: lipa has been classified as Green List (High Evidence).

25 Jul 2018, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: LIPA were set to Neonatal and Adult Cholestasis; lysosomal acid lipase deficiency; cholestasis; Cholesteryl ester storage disease 278000; Wolman disease 278000

25 Jul 2018, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: LIPA were set to 23485521; 26137452; 8617513; 29702543; 29731497; 8598644; 7759067; 8254026

25 Jul 2018, Gel status: 3

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: LIPA was changed from to BIALLELIC, autosomal or pseudoautosomal

25 Jul 2018, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: lipa has been classified as Green List (High Evidence).

21 Jun 2018, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

Victorian Clinical Genetics Services was added to LIPA. Panel: Cholestasis

18 May 2018, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

LIPA was added to Cholestasis panel. Sources: Emory Genetics Laboratory

18 May 2018, Gel status: 1

Created

Ellen McDonagh (Genomics England Curator)

LIPA was created by Ellen McDonagh