Table of variants:
Project 6 News
One aim of Project 6 on this Conte Proposal was to identify genetic variants in a collection of families with circadian phenotypes. Some of these will represent causative mutations and many will be known and newly recognized polymorphisms. Some “novel polymorphisms” may, in fact, have subtle functional consequences that contribute to morningness/eveningness but insufficient to cause a Mendelian circadian phenotype. Availability of this data in the public domain will allow other investigators with collections of individuals from the general population (with phenotypic data on morningness/eveningness) to test such variants for an association with morningness or eveningness.
Deep resequencing of candidate circadian genes in a large collection (~64) of probands from familial advanced sleep phase syndrome (FASPS) and familial delayed sleep phase syndrome (FDSPS) families revealed many polymorphisms (~180 in these 20 genes) and potentially causative mutations (~20 in these 20 genes). All of these families have phenotypes that appear to be autosomal dominant traits by segregation. Many of the variants we found are known polymorphisms. However, there was a large collection of variants that are not currently in the public databases. The variants that are considered to NOT be causative are cataloged here (potentially causative mutations are currently being evaluated further and will be placed into the database as soon as additional data implicating them in causation (or not) has been generated). Investigators with interest in specific genes may contact Drs. Ying-Hui Fu or Louis Ptacek. If mutations are not actively being pursued for that gene, a collaborative arrangement may be possible for such potential collaborators to study these mutations in vitro and/or in vivo.
Variants are considered “not causative” if they are:
1) known polymorphisms
2) very common in our collection of probands
3) do not segregate with the FASPS or FDSPS phenotype in the family(ies) of probands in whom the variant was found
4) synonymous changes (N.B. in rare cases these might in fact be causative due to altered mRNA stability or alter splicing)
In the table of variants (PDF, DOC), the first column highlights changes in coding sequence (both synonymous and non-synonymous). The third column shows the number of each genotype (note the total number varies from one to the next—because there were different #s of failed samples for each amplicon). Thus, for example, the first one for NPAS2: freq of A=116/118 B=2/118. The last column notes which are known SNPs vs newly recognized variants.
The ethnicity of the sample is largely Caucasian and thus, these allele frequencies may not reflect those seen in other populations.