Intellectual disabilityGene: LSS
PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal.
They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.
Created: 12 Nov 2020, 3:04 p.m. | Last Modified: 12 Nov 2020, 3:04 p.m.
Panel Version: 3.522
11 individuals from 6 families where ID is reported plus the family reported by Romano et al: families where ID is a feature outnumber the families with apparently isolated cataract/hypotrichosis. This is unlikely to be coincidental. Reports of phenotype expansion/allelic disorders are increasingly common. There is a second opportunity to assess genotype-phenotype correlation at variant review/MDT. We have therefore rated this gene Green for ID.
Created: 9 Feb 2020, 8:56 a.m. | Last Modified: 9 Feb 2020, 8:56 a.m.
Panel Version: 3.0
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Comment on list classification: Comment on list classification: Advice from clinical team confirmed that LSS should be kept as Amber as "In view of the variability of phenotypes / presentations reported I think amber and watchlist whilst further information is gathered would be appropriate."
Created: 1 Jul 2019, 10:21 a.m. | Last Modified: 1 Jul 2019, 10:21 a.m.
Panel Version: 0.196
Comment on list classification: Gene status was changed to Amber due to a expert review by Konstantinos Varvagiannis. PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants.
LSS associated with 2 OMIM phenotypes. Hypotrichosis 14 (#618275) and Cataract 44 (#616509). Neither are phenotypically relevant to ID.
PMID: 30723320 [Besnrard et al, 2019] reports phenotype of 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)
However 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.
Also 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.
Due to conflicting evidence rating gene as Amber until discussion with the clinical team.
Created: 4 Jun 2019, 4:32 p.m. | Last Modified: 26 Jun 2019, 10:28 a.m.
Panel Version: 0.195
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).
Created: 14 Feb 2019, 8:44 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly
Tag watchlist tag was added to gene: LSS.
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)
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