Comparison of pan‐ethnic and ethnic‐based carrier screening panels for individuals of Ashkenazi Jewish descent

Abstract

The intent of carrier screening is to identify individuals at risk for having a child with a genetic disorder. American College of Medical Genetics and Genomics (ACMG) guidelines currently recommend that individuals of Ashkenazi Jewish (AJ) descent be screened for carrier status for nine disorders. However, a joint statement from five professional organizations acknowledges benefits of expanded carrier screening and this is becoming common practice. To better understand the impact of expanded carrier screening for the AJ population, we performed a retrospective analysis comparing detection rates for AJ individuals screened by two targeted panels: a pan‐ethnic panel comprising 87 disorders and an AJ panel comprising an 18‐disorder subset of the pan‐ethnic panel. We also extrapolated the detection rates for the 18 AJ disorders from the pan‐ethnic panel data and for the nine ACMG‐recommended disorders using data from both panels. We found that with the pan‐ethnic panel 431/1150 (37.5%) individuals were carriers of at least one disorder, compared to 319/1248 (25.6%) individuals with the AJ panel. If the pan‐ethnic panel cohort were tested in the AJ panel or for the nine ACMG‐recommended disorders, the detection rates would have been 280/1150 (24.3%) and 207/1150 (18.0%) respectively. Therefore, the pan‐ethnic expanded carrier screening panel of 87 disorders increased the carrier detection rate in AJ individuals by approximately 50% and 100%, respectively, compared with a panel of 18 disorders considered relevant to the AJ population and the ACMG‐recommended disorders. Twenty disorders accounted for the difference in carrier detection rates between the pan‐ethnic and AJ panels. Of these, three were among the 10 most commonly identified disorders. Our findings reinforce published data that targeted AJ panels are less effective than a pan‐ethnic panel in carrier detection among AJ individuals and provide metrics to address the impact of expanded carrier screening in this population.

Pathogenic variant‐based preconception carrier screening in the Israeli Jewish population

“…For individuals of AJ origin, the CCR found in our study was 58.5% and therefore higher than the 37.5% (1:2.7) 19 and 40%…”

“…For individuals of AJ origin, the CCR found in our study was 58.5% and therefore higher than the 37.5% (1:2.7) 19 and 40% (1:2.5) 20 published in AJ cohorts, or the 36% (1:2.8) 21 reported in a pan‐ethnic population.…”

“…16 Historically, this population has been an ideal model for carrier screening due to known founder variants and endogamy. 19,20,22 In our study, the majority of tested individuals ($66% of all alleles) were of AJ descent. 23,24 However, the list of chosen diseases included some common mild conditions and some with variable expressivity, not tested in our carrier screening panel, which could explain the high rate of ARCs for the fewer genes tested.…”

“…In Israel, this community accounts for 55% of all Jews 16 . Historically, this population has been an ideal model for carrier screening due to known founder variants and endogamy 19,20,22 . In our study, the majority of tested individuals (~66% of all alleles) were of AJ descent.…”

Real-world genetic screening with molecular ancestry supports comprehensive pan-ethnic carrier screening

“…We refer to this 2-gene panel as the standard pan-ethnic panel (SPEP). The second panel is comprised of 77 genes ( ABCC8, ABCD1, ACADM, ACADVL, ACAT1, AGA, AGXT, AIRE, ALDOB,ALPL, ARSA,ASL,ASPA,ATP7B,BBS1, BBS2, BCKDHB, BLM, BTD, CBS, CEP290, CHRNE, CLRN1, CNGB3, COL7A1, CPT2, CTFR, CYP21A2, CYP27A1, DHCR7,DHDDS, DLD, DMD, ELP1,F9, FAH, FANCC, FKRP, FKTN, FMR1, G6PC, GAA, GALT, GBA, GBE1, GJB2, GLA, GNPTAB, HBA1/2, HBB, HEXA, HPS1, HPS3, IDUA, MCCC2, MCOLN1, MLC1, MMACHC, MMUT, NEB, NPHS1, OTC, PAH, PCDH15, PKHD1, PMM2,RARS2,RS1,SLC26A2, SLC26A4, SLC37A4, SLC6A8, SMN1, SMPD1, TMEM216, USH2A ) that are recommended by ACMG guidelines and included in our CS-283 panel 48 . The third panel represents a set of 283 genes included on Sema4’s most comprehensive expanded carrier screening products and is referred to as CS-283.…”