Genetic Work Up in a Consanguineous Family with Variable Phenotypes Including Cognitive Regression, Spasticity, and Visual Impairment
Matthew J. Woodward1, Marrisa Lafreniere1, Michael Korsmo1, Brooke Heffernan1, Emily Forbes1
1Neurology, University of Colorado School of Medicine
Objective:
Describe genetic work up in consanguineous Afghani family with variable severity of visual impairment, abnormal brain imaging, cognitive changes, spasticity, and leg weakness.
Background:
Newly discovered genetic variants continue to be described, especially in those not of European descent. Rare genetic variants in minoritized communities may reveal novel, pathogenic variants and disease presentations. Genetic testing in these families may also inform risk to other family members to assist family planning.
Results:
A 29-year-old sister and 33-year-old brother from Afghanistan with consanguineous parents presented for spasticity and visual changes. The brother was developmentally normal until 8 years old, when he began to develop leg weakness, visual impairment, and developmental regression. Examination demonstrated minimal communication, ability to follow simple commands, and diffuse hyperreflexia greater in the lower extremities. Work up revealed brain atrophy on MRI. Genetic testing with whole exome sequencing (WES) revealed homozygous, likely pathogenic variant in EYS, as well as homozygous variants of uncertain significance in FA2H and GRID2.
The sister was developmentally normal. At 20 years of age, she began to develop leg weakness and visual changes. Examination revealed proximal mild leg weakness, loss of ankle dorsiflexion, leg spasticity, and diffuse hyperreflexia worse in the lower extremities. On work up, she was found to have retinitis pigmentosa and cerebellar atrophy with leukodystrophy on MRI. Genetic testing with WES revealed the same homozygous mutations in FA2H and EYS as her brother.
Conclusions:
Three different autosomal recessive genetic mutations were identified in this consanguineous family that are likely causing pathological phenotypes in 5 of 6 siblings. The FA2H variants are observed in homozygous state in those who have features of FA2H-related neurodegeneration within this family. This variant is not found in population databases (gnomAD). We propose this variant is pathologic in this family. The GRID2 variant potentially explains phenotypic differences within the family.