EP 144: Research Roundup with Dr. Veera: breakthroughs in developmental disorders, Parkinson's, SLE, and Alzheimer's

The Genetics Podcast

0:00 Introduction

1:40 A recurrent de novo mutation in a noncoding region of a small nucleolar RNA gene that has been identified as one of the most common causes of neurodevelopmental disorders

• This pathogenic variant escaped notice for years because it was not located in a protein coding region of the genome
• It now shows potential as a target for various therapeutic developments for children with developmental disorders
• See the original paper here: De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders

20:30 A new gene, RAB32, linked to Parkinson’s disease through exome sequencing of families impacted by PD

• Direct interactions with the LRRK2 gene through its armadillo domain, resulting in a gain of function missense mutation
• How RAB32 was discovered as a significant mutation in PD research
• The strong therapeutic implications of RAB32 and LRRK2
• See original papers: RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses and Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease

35:30 Gaining insights from rare, monogenic conditions: A monogenic cause of early onset systemic lupus erythematosus (SLE)

• Making discoveries by following a biological thread, a rare privilege enjoyed by few fields like immunology
• See original paper here: Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
• A related paper from two years ago on SLE and the TLR7 gene: TLR7 gain-of-function genetic variation causes human lupus

49:30 Alzheimer’s disease: Old genes, new insights

• Redefining research goals to make better sense of old discoveries, in addition to making new discoveries
• deCODE’s previous work on the homozygosity deficit inference
• APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease
• Homozygosity for R47H in TREM2 and the Risk of Alzheimer’s Disease

59:00 Closing remarks

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