Early onset or syndromic epilepsy

Gene: LSS

I don't know

Kept rating as Amber based on Amber post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:27 a.m. | Last Modified: 9 Sep 2019, 10:27 a.m.

Panel Version: 1.316

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

I don't know

Besnard et al, 2019 - Expansion of the phenotypic spectrum of LSS to AR neuroectodermal syndrome. 11 individuals from 7 unrelated families - all aff with alopecia, scaly skin, other ectodermal abnormalities, variable MRI abnormalities and neurological symptoms. All aff hom/compound het and parents carriers. Epilepsy in 8/11 individuals. 2 splicing variants detected - minigene assays confirmed the effect on mRNA splicing and exon skipping.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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, 10:20 a.m. | Last Modified: 1 Jul 2019, 10:20 a.m.

Panel Version: 0.46

Currently rated as Amber until advice from Genomics England Clinical Team.

The gene has been well studied but has conflicting phenotype evidence from different groups.  The most recent paper PMID:30723320 has alopecia, and ID as a consistent phenotype throughout the identified individuals. Epilepsy also affects a majority of individuals. There are two papers where LSS is associated with cataracts PMID:26200341 and PMID:29016354(abstract only available). The first paper gives no other phenotypes associated to the individuals. The second paper PMID:29016354 lists baldness as a phenotype associated to the affected individual.
A paper by Romano PMID:30401459 reported on 3 unrelated families with biallelic mutations in the LSS gene all reported to have Hypotrichosis.  ID was a feature in 2 siblings from 1 family but was considered to be coincidental by the authors.

Created: 26 Jun 2019, 11:21 a.m. | Last Modified: 27 Jun 2019, 12:39 p.m.

Panel Version: 0.37

I don't know

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

Created: 14 Feb 2019, 9:03 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly

Publications

• 30723320