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| Intellectual disability - microarray and sequencing v3.1513 | LSS |
Arina Puzriakova Tag watchlist was removed from gene: LSS. Tag for-review was removed from gene: LSS. |
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| Intellectual disability - microarray and sequencing v3.1510 | LSS | Sarah Leigh commented on gene: LSS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1509 | LSS |
Arina Puzriakova Source Expert Review Green was added to LSS. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v3.681 | LSS | Eleanor Williams changed review comment from: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; to: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS, as agreed with Genomics England clinicians. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.681 | LSS | Eleanor Williams Tag for-review tag was added to gene: LSS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.681 | LSS | Eleanor Williams edited their review of gene: LSS: Added comment: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.522 | LSS | Eleanor Williams commented on gene: LSS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | LSS | Zornitza Stark reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30723320; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.981 | LSS | Catherine Snow Tag watchlist tag was added to gene: LSS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.978 | LSS |
Catherine Snow Source Expert Review was added to LSS. Source Expert Review Amber was added to LSS. Added phenotypes Cataract 44, Hypotrichosis 14, 616509, 618275 for gene: LSS Publications for gene LSS were changed from 30723320; 30401459 to 30723320; 26200341; 30401459; 29016354 Rating Changed from No List (delete) to Amber List (moderate evidence) |
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| Intellectual disability - microarray and sequencing v2.632 | LSS |
Konstantinos Varvagiannis gene: LSS was added gene: LSS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LSS were set to 30723320; 30401459 Phenotypes for gene: LSS were set to Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly Penetrance for gene: LSS were set to Complete Review for gene: LSS was set to GREEN Added comment: DD and ID seem to be among the features observed in some individuals with biallelic LSS mutations, although the clinical presentation appears to be highly variable. PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants. One additional subject from a seventh family was found to harbor only a missense SNV (in the maternal allele) while the transcript corresponding to the other (/paternal) allele was less expressed upon RNA studies from patient fibroblasts. The allelic imbalance and the phenotypic overlap with the other individuals of the study were thought to be explained by an LSS defect. The phenotype consisted of total alopecia (11/11) with additional dermatological features in most (9/11), hypotonia (7/11), DD with variable degrees of ID (11/11 both), epilepsy (8/11), microcephaly and genital anomalies in few. Cataracts were not noted in any individuals. The authors suggest that the phenotype corresponds to that observed in a neuroectodermal syndrome previously known as APMR (alopecia with mental retardation - other genes or loci earlier proposed). Variants included: 7 missense SNVs, 1 nonsense, 1 frameshift, 2 splice variants (c.1109+2T>C / c.1194+5G>A - using NM_002340.5). Using a minigene assay the latter variants were confirmhed (both) to affect splicing, at least to some important extent. However the splicing defect for one SNV (c.1194+5G>A - skipping of exon 12) was not confirmed upon RNA studies from blood samples of the respective individuals but an allelic balance in favor of the other allele instead (due to presumed utilisation of an alternative splice site, introduction of a premature stop codon and NMD). Allelic imbalance is discussed for the individual with the single LSS variant but not shown. Variants did not show clustering (also upon 3D modelling). Lanosterol synthase converts (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Quantification of cholesterol and its precursors in affected individuals did not however reveal any important imbalance. As most individuals harbored an allele with missense variant, and mice homozygous for an allele with absent LSS activity show variable lethality, residual LSS activity is suggested for the individuals studied. Several other disorders affecting cholesterol biosynthesis present overlapping features eg. DD/ID in Lathosterolosis, Desmosterolosis, Smith-Lemli-Opitz syndrome (in this case also genital anomalies), etc or cutaneous anomalies in others. A neurodevelopmental phenotype in animal models for LSS deficiency is not commented. ----- Based on the discussion of the current article (and OMIM): Earlier studies [PMIDs : 26200341, 29016354 - Zhao et al 2015 and Chen and Liu 2017 respectively] found biallelic missense in individuals with congenital cataracts. DD/ID were not commented/observed. The subject reported by Chen had baldness and genital defects. Shumiya cataract rats due to mutation in Lss gene recapitulate the specific human phenotype [PMID: 16440058 and OMIM]. Cataract was not a feature in any of the individuals of the present study. The corresponding entry for this phenotype in OMIM is Cataract 44 (#616509). PMID: 30401459 [Romano et al, 2018] reported biallelic LSS mutations in 3 unrelated families with hypotrichosis. Intellectual disability was a feature in 2 sibs from 1 non-consanguineous family (among the three). ID was considered to be coincidental by the authors. The respective entry in OMIM is Hypotrichosis 14 (#618275). ----- LSS is not included in the DD panel of G2P, nor in gene panels for ID offered by diagnostic laboratories. ----- As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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