Abstract
Purpose :
Biallelic mutations in LAMA1 (laminin subunit alpha 1) (OMIM #150320) cause Poretti-Boltshauser Syndrome (PBS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia and retinal dystrophy. Only 32 variants nearly all loss-of-function, have been previously reported in 29 patients from 23 families. Clinical presentation included consistent as well as unspecific and variable features such as intellectual disability. Here we report 3 affected siblings, homozygous for a novel frameshift mutation in LAMA1 and their detailed retinal manifestations.
Methods :
Whole genome sequencing (Illumina 150bp paired-end reads, average x30 read-depth) was conducted on members of a consanguineous family with myopia and retinal dystrophy in three of five adult children. Filtering for rare variants in known retinal genes and genome-wide variants in shared homozygous regions in affected individuals was employed. Clinical evaluation included full ophthalmic examination, detailed colour, autofluorescence retinal imaging, retinal optical coherence tomography (OCT) and electroretinography.
Results :
Genetic analysis revealed a novel homozygous LAMA1 frameshift variant, c.1492del p.(Arg498GlyfsTer25), in two male and one female affected siblings. Two had oculomotor apraxia in childhood; none had symptoms nor signs of neurological failure as adults. Corrected visual acuities ranged from 6/6 to 6/24. All three had myopia, and a qualitatively similar retinopathy of wide-ranging severity, involving pigmentary changes in the temporal retina in the two lesser affected siblings and in the posterior pole in the more severely affected sibling. Electrophysiology showed mild to severe cone rod dystrophy.
Conclusions :
This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in three siblings and these exhibit much variability. Biallelic mutations should be considered in myopia and retinopathy, even in the absence of systemic signs.
This is a 2021 ARVO Annual Meeting abstract.