Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome

Shahram Yazdani; Anish Badjatiya; Naghmeh Dorrani; Hane Lee; Wayne W Grody; Stanley F Nelson; Katrina M Dipple

doi:10.1016/j.ymgmr.2020.100582

Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome

Mol Genet Metab Rep. 2020 Apr 6:23:100582. doi: 10.1016/j.ymgmr.2020.100582. eCollection 2020 Jun.

Authors

Shahram Yazdani¹, Anish Badjatiya², Naghmeh Dorrani¹, Hane Lee^{2

3}, Wayne W Grody^{1

2

3}, Stanley F Nelson^{1

2

3}, Katrina M Dipple^{1

2}

Affiliations

¹ Departments of Pediatrics and Mattel Children's Hospital at UCLA, Los Angeles, CA, United States of America.
² Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
³ Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.

Abstract

We report two brothers with severe global cognitive and motor delay, cortical visual impairment and sick sinus syndrome who were born to consanguineous parents. Standard genetic evaluations did not reveal the cause of their mental retardation. As expected, chromosomal microarray (CMA) revealed extensive regions of homozygosity. Exome sequencing revealed that both affected boys were homozygous for a nonsense mutation in the G-protein β5 (GNB5) gene (NM_016194.3:c.1032C > G; Tyr344Ter), and that the parents were carriers of this mutation. No other DNA variants that were explanatory for the sick sinus or the developmental delay/intellectual disability were identified, and no other clinical parameters are likely to have contributed to this unusual combination of phenotypes. The neurologic features of our patients are more severe than those of most of the other patients previously reported with GNB5 variants, probably because of the homozygous, complete loss-of-function (nonsense/stop-gain) nature of their variant, and their clinical course has been monitored for longer duration.

Keywords: Blindness; Cardiac arrhythmia; Encephalopathy; GNB5; Genetic disorder; Seizure.