Novel LSS Variants in Alopecia and Intellectual Disability Syndrome: New Case Report and Clinical Spectrum of LSS-Related Rare Disease Traits

Authors

Hasnaa M Elbendary
Dana Marafi
Ahmed K Saad
Rasha Elhossini
Ruizhi Duan
Karima Rafat
Shalini N Jhangiani
Richard A Gibbs
Davut Pehlivan
Daniel G Calame
Jennifer E Posey
James R Lupski
Maha S Zaki

Publication Date

9-1-2023

Journal

Clinical Genetics

DOI

10.1111/cge.14348

PMID

37157980

PMCID

PMC10524748

PubMedCentral® Posted Date

9-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Male, Humans, Intellectual Disability, Mutation, Rare Diseases, Alopecia, Phenotype, Syndrome, LSS-related phenotypes, intellectual disability, hypogenitalism, cerebellar abnormalities, alopecia

Abstract

Pathogenic biallelic variants in LSS are associated with three Mendelian rare disease traits including congenital cataract type 44, autosomal recessive hypotrichosis type 14, and alopecia-intellectual disability syndrome type 4 (APMR4). We performed trio research 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) variant alleles. Rare features associated with APMR4 such as cryptorchidism, micropenis, mild cortical brain atrophy and thin corpus callosum were detected. Previously unreported APMR4 findings including cerebellar involvement in the form of unsteady ataxic gait, small vermis with prominent folia, were noted. A review of all reported variants to date in 29 families with LSS-related phenotypes showed an emerging genotype-phenotype correlation. Our report potentially expands LSS-related phenotypic spectrum and highlights the importance of performing brain imaging in LSS-related conditions.