Novel LSS variants in alopecia and intellectual disability syndrome: New case report and clinical spectrum of LSS‐related rare disease traits

Abstract

AbstractPathogenic 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.