Hello,

 

I am writing this email to reserve a spot in next week’s Biostats clinic on Thursday January 19^th for clinical and health research.  The summary for the project is outlined below. In essence this is a study where we examined rare variants in the ALPL gene that were available in Biovue and looked for expected associations as well as a new associations which were discovered via PheWAS. We had 180 cases plus matched controls which were manually reviewed by two reviewers that were blinded.  The manual chart review of the patients record in the SD is in Excel.  Additionally we have some very basic statistics in R and summarized below. We would appreciate some advice from bio-stats on better visualization/representation of the data. Thank you for your consideration.

 

 

Project Summary:

 

Twelve rare variants in the tissue-nonspecific alkaline phosphatase (TNSALP) gene associated with bone and gynecological disease.

 

Context:  Mutations in TNSALP cause hypophosphatasia (HPP) and lead to well described bone and dental disease. Although HPP is usually detected by a low serum alkaline phosphatase (AlkP), we hypothesized that some patients with bone or dental disease may have undiagnosed variants in TNSALP.

Objective: To assess the prevalence of  new TNSALP variants in the Vanderbilt DNA database (BioVU), to discover phenotypic associations related to bone, dental and other organ dysfunction and the accuracy HPP diagnosis.

Design: We surveyed all patients in BioVU that had a variant(s) in TNSALP. We then reviewed the de-identified medical records of the variant patients for phenotype related to bone, dental and other organ dysfunction. Where we found likely associations, we used age and gender matched controls without TNSALP variants to determine statistical likelihood of validation.

Setting and Patients: BioVU is composed of DNA from patients having phlebotomy in the outpatient setting at Vanderbilt University Medical Center. These are unselected as to race, age or gender.

Main Outcome Measures: The main outcome measures were the number of patients with new variants and their prevalence, the association of variants with bone, dental and other disease, and the frequency of accurate diagnosis.

Results: The number of patients with TNSALP sequencing in BioVU was 25,822.  We found 180 patients with  eight new variants, the majority of which had the known phenotype of bone and  dental disease. We additionally identified a statistically significant, new and unexpected phenotypic association of gynecological disease.  Surprisingly the mean alkaline phosphatase level for both cases and controls were within the normal range. None of the patients in the SD had the diagnosis of HPP, even with low alkaline phosphatase levels as a clue.   

Conclusions:  Variants in TNSALP are likely causal of bone and dental disease in patients with and without low alkaline phosphatase. Gynecological disease appears to be associated with variants in TNSALP, a new observation. Physicians may not be aware of the association of low alkaline phosphatase with HPP, an important finding since therapy is now available.    

 

Kathryn McCrystal Dahir, MD
Associate Professor of Medicine

Associate Fellowship Director
Vanderbilt University Medical Center
Endocrinology and Diabetes
8210 Medical Center East
1215 21st Avenue South
Nashville, TN 37232-8148
615 343-8332