Proteinuric renal disease
Gene: LCAT
Have a family who presented with proteinuric kidney disease; homozygosity/compound heterozygosity is required for kidney disease, heterozygosity = cloudy corneas which these patients may not get. Children and young adults present with proteinuria and hypercholesterolaemia in the face of an absent/low HDL so full lipid panel required or diagnosis can be missed (all proteinuric renal disease can lead to hypercholesterolaemia). This progresses to end stage renal failure without intervention by 20's. Renal biopsy can be diagnostic but sometimes confused with storage disorders; can masquerade as membranous nephropathy. Advantage of early diagnosis is early intervention that once recombinant LCAT is available (2022/23) renal failure can be prevent - provided this is started before CKD beds in. Rate of decline in GFR to stage 4/5 CKD in untreated patients (can start statins and B vitamins as well as ACE/ARB which also help) is max. 10 years. We are submitting a case report.Created: 25 Feb 2021, 12:57 p.m. | Last Modified: 25 Feb 2021, 12:57 p.m.
Panel Version: 2.48
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
proteinuric renal disease; pseudo-membranous nephropathy; unexplained renal failure in young adults
Publications
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 7 Mar 2022, 11:51 p.m. | Last Modified: 7 Mar 2022, 11:51 p.m.
Panel Version: 2.75
Comment on list classification: Leaving rating as amber for now, but with a green rating recommendation following GMS review. There are several reported cases where proteinuria is a prominent feature, plus a green expert review reporting a case of a family presenting with proteinuric kidney diseaseCreated: 7 Oct 2021, 4:25 p.m. | Last Modified: 7 Oct 2021, 4:25 p.m.
Panel Version: 2.58
Several cases in which proteinuria was noted in patients with LCAT deficiency are reported, including:
PMID: 21315357 - Holleboom et al 2011 - report 3 siblings (age 17, 12 and 3 years) in a family with HDL deficency. The 17-year-old was referred for renal pathology compatible with a metabolic disorder, including FLD. Corneal opacification and proteinuria were observed in all three and they were found to be homozygous for a missense variant in LCAT which disrupted the second disulfide. LCAT protein and activity were undetectable in the patients' plasma. The parents and an unaffected brother were heterozygous for the variant.
PMID: 30201532 - Hanna et al 2018 - report a 29-year-old female who initially presented with discomfort, photophobia, and decreased vision in both eyes. Bilateral corneal clouding, severely reduced HDL cholesterol, and proteinuria were noted. Two heterozygous mutations of the LCAT gene were identified: c.321C>A (p.Tyr107 *) and c.1034C>T (p.Thr345Met)
PMID: 29535099 - Morales et al 2018 - report 44-year-old woman diagnosed with corneal dystrophy and anaemia. Analysis showed proteinuria between 1 and 2 g/day. A missense homozygous variant in the LCAT gene c.368G>C (p (R123p)) was identified.
PMID: 22108153 - Roshan et al 2011 - report a 50-year-old man with uncontrolled hypertension, hemolytic anemia, and renal insufficiency. He had a long history of proteinuria (3+ for at least 30 years). He was found to have diffuse marked corneal opacification. Sequencing the LCAT gene showed a homozygous missense mutation. His parents were first cousins.
Cases presenting with proteinuria with a LCAT deficiency diagnosis but no molecular analyses:
PMID: 28508023 - Balwani et al 2016 - a patient with nephrotic syndrome, which renal biopsy revealed classic features of LCAT deficiency. There was no obvious family history and the patient was without any corneal deposits and normal HDL-C levels. NOTE NO MOLECULAR DIAGNOSIS.
PMID: 25657982 - Mahdi Althaf et al 2015 - 30-year-old male was referred for persistent proteinuria. Bilateral corneal ring opacities were noted. Renal biopsy findings were consistent with LCAT deficiency.Created: 7 Oct 2021, 4:11 p.m. | Last Modified: 7 Oct 2021, 4:11 p.m.
Panel Version: 2.55
Comment on list classification: Changing the rating from green to amber until a review of the degree of proteinuria in patients with Norum disease has been carried out.Created: 9 Jul 2019, 1:05 p.m. | Last Modified: 9 Jul 2019, 1:05 p.m.
Panel Version: 1.218
This gene was part of an initial gene list collated by Elizabeth Watson, North Bristol NHS Trust, February 2019 on behalf of the GMS Renal Specialist Test Group. Gene Symbol submitted: LCAT; Suggested initial gene rating: amber; Evidence for inclusion: none provided; Other comments: Proteinuria presents as part of LCAT-deficiency syndrome. Multiple publications.Created: 4 Feb 2019, 10:41 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Norum disease, OMIM:245900; Norum disease, MONDO:0009515; LCAT DEFICIENCY
Publications
LCAT Inclusion of this as a green gene on this panel is appropriate, based on the review in the Undiagnosed metabolic disorders panel and the views of clinical expert, Dr Arianna Tucci, UCL.Created: 20 Mar 2017, 12:34 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Tag Q4_21_rating was removed from gene: LCAT. Tag Q4_21_NHS_review was removed from gene: LCAT.
Source Expert Review Green was added to LCAT. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q4_21_NHS_review tag was added to gene: LCAT.
Gene: lcat has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: LCAT were changed from Norum disease #245900 to Norum disease, OMIM:245900; Norum disease, MONDO:0009515; LCAT DEFICIENCY
Publications for gene: LCAT were set to 6078131
Tag Q4_21_rating tag was added to gene: LCAT.
Gene: lcat has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: LCAT were changed from to Norum disease #245900
Source NHS GMS was added to LCAT. Rating Changed from Green List (high evidence) to Green List (high evidence)
This gene has been classified as Green List (High Evidence).
LCAT was created by sleigh
LCAT was added to Proteinuric renal diseasepanel. Sources: Expert Review