Variability of retinopathy consequent upon novel mutations in LAMA1

ABSTRACT

Purpose

Bi-allelic mutations in LAMA1 (laminin 1) (OMIM # 150320) cause Poretti-Boltshauser Syndrome (PTBHS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia, and retinal dystrophy. Only 38 variants, nearly all loss of function have been reported. Here, we describe novel LAMA1 variants and detailed retinal manifestations in two unrelated families.

Methods

Whole-genome sequencing was conducted on three siblings of a consanguineous family with myopia and retinal dystrophy and on a child from an unrelated non-consanguineous couple. Clinical evaluation included full ophthalmic examination, detailed colour, autofluorescence retinal imaging, retinal optical coherence tomography (OCT), fluorescein angiography under anesthesia, and pattern and full-field electroretinography.

Results

Genetic analysis revealed a novel homozygous LAMA1 frameshift variant, c.1492del p.(Arg498Glyfs *25), in the affected siblings in family 1 and a novel frameshift c.3065del p.(Gly1022Valfs *2) and a deletion spanning exons 17–23 in an unrelated individual in family 2. Two of the three siblings and the unrelated child had oculomotor apraxia in childhood; none of the siblings had symptoms of other neurological dysfunction as adults. All four had myopia. The affected siblings had a qualitatively similar retinopathy of wide-ranging severity. The unrelated patient had a severe abnormality of retinal vascular development, which resulted in vitreous haemorrhage and neovascular glaucoma in the left eye and a rhegmatogenous retinal detachment in the right eye.

Conclusions

This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in four patients from two families, and these exhibit significant variability with evidence of both retinal dystrophy and abnormal and incomplete retinal vascularisation.

KEYWORDS:

• LAMA1
• Poretti-Boltshauser syndrome
• cerebellar dysplasia
• oculomotor apraxia
• myopia
• retinal dystrophy

Acknowledgements

This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13816810.2022.2076283.

Additional information

Funding

This work is supported by the NIHR-BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology and the Cambridge NIHR Biomedical Research Centre and NIHR Bioresource for Rare Diseases (NIHRBR-RD). GA is funded by a Fight For Sight UK Early Career Investigator Award (5045/46) and NIHR-BRC at Great Ormond Street Hospital Institute for Child Health