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Early onset or syndromic epilepsy v8.139 LSS Arina Puzriakova Tag Q3_25_promote_green was removed from gene: LSS.
Early onset or syndromic epilepsy v8.134 LSS Achchuthan Shanmugasundram commented on gene: LSS: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 LSS Arina Puzriakova Source Expert Review Green was added to LSS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.41 LSS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.; to: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

After seeking clinical opinion, it has been decided to recommend this gene for promotion to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia; Abnormality of the skin; Microcephaly; Cataract 44, 616509, Hypotrichosis 14, 618275; Seizures; Abnormality of the genital system; Hypotonia; Intellectual disability; Global developmental delay to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram edited their review of gene: LSS: Changed publications to: 30723320, 37157980
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 37157980; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.331 LSS Rebecca Foulger Source Wessex and West Midlands GLH was added to LSS.
Early onset or syndromic epilepsy v1.330 LSS Rebecca Foulger Source NHS GMS was added to LSS.
Early onset or syndromic epilepsy v1.316 LSS Rebecca Foulger commented on gene: LSS: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.262 LSS Rebecca Foulger reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.261 LSS Helen Lord reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.177 LSS Catherine Snow Source Expert Review was added to LSS.
Source Expert Review Amber was added to LSS.
Added phenotypes Cataract 44, 616509, Hypotrichosis 14, 618275 for gene: LSS
Publications for gene LSS were changed from 30723320 to 30723320; 26200341; 30401459; 29016354
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.13 LSS Konstantinos Varvagiannis gene: LSS was added
gene: LSS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 30723320
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 unknown
Review for gene: LSS was set to AMBER
Added comment: Epilepsy was observed in at least 6 individuals from 4 unrelated families (7 different variants). However other individuals with biallelic LSS mutations and primarily neuroectodermal phenotype or others (hypotrichosis or congenital cataract) did not manifest seizures. As a result this gene can be considered for inclusion possibly as amber.

Copied from the ID panel (only the relevant publication included here):
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.
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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).
Sources: Literature