2018 ISPD Conference

Pan-ethnic expanded carrier testing for branched chain amino acid disorders
Desiree Fiorentino1, Jonah Bardos2, Catherine Terhaar3, Katherine Hill-Harfe4, Ryan Longman5

1University of Miami, coral gables, florida, United States
2University of Miami, Miami, FL, United States
3Progenity, Rockford, MI, United States
4Progenity, Inc., Ann Arbor, MI, United States
5University of Miami Miller School of Medicine, Miamia, FL, United States
Objectives
Branched-chain organic acidurias/acidemias are a group of autosomal recessive conditions characterized by impaired catabolism of branched-chain amino acids (BCAA). Clinical presentation ranges from severe, neonatal-onset with metabolic distress to a chronic, progressive form characterized by failure to thrive, developmental delay, and hypotonia. Historically, carrier screening guidelines were ethnicity-based and did not include testing for BCAA disorders. New technologies and increasing ethnic diversity have enabled expanded carrier testing as an acceptable clinical practice. This study assesses how many individuals tested positive for four different BCAA disorders when a pan-ethnic expanded carrier screening panel was implemented.
Methods
A retrospective database analysis was performed on samples received for expanded carrier testing via a commercially-available genotyping platform. The number of patients tested ranged from 24,158 to 84,413, depending on the disorder. Patients screened were divided into nine self-reported ethnicity categories. The expected numbers of carriers for maple syrup urine disease (MSUD), isovaleric acidemia (IVA), methylmalonic aciduria (MMA), and propionic acidemia (PA) were calculated based on established carrier frequencies specific to each ethnicity and the assay’s detection rates. The number of observed-to-expected carriers for each disease were compared. Chi-squared analysis was performed to assess for statistical significance (p<0.05).
Results
Concordance was seen in the number of observed-to-expected carriers across most ethnicities and branched chain amino acid disorders.  There were, however, statistically greater numbers of carriers of MSUD type 1b observed vs. expected amongst Caucasians (24 vs. 14.8, p= 0.017) and amongst patients who designated themselves as other or mixed ethnicity (11 vs. 5.9, p=0.013). The number of observed carriers for PA, PCCB-related, amongst individuals reporting Asian ethnicity was also greater than expected (6 vs. 2.02, p=0.005).
Conclusions
The number of observed carriers for branched chain amino acid disorders amongst certain ethnicities were significantly greater than expected based on historical carrier rate data. With increased mixing of the population, self-reported ethnicities may no longer be an adequate way to determine which couples are at highest risk for having children affected by these morbid and incurable, but potentially treatable, disorders. Pan-ethnic expanded carrier testing will increase the detection of carriers for branched chain amino acid disorders when compared with ethnicity-based screening recommendations, and allows for improved reproductive counseling.