A robust pipeline for ranking carrier frequencies of autosomal recessive and X-linked Mendelian disorders

Abstract

Single gene disorders are individually rare but collectively common leading causes of neonatal and pediatric morbidity and mortality. Both parents or the mothers of affected individuals with autosomal recessive or X-linked recessive diseases, respectively, are carrier(s). Carrier frequencies of recessive diseases can vary drastically among different ethnicities. This study established a robust pipeline for estimating and ranking carrier frequencies of all known 2699 recessive genes based on genome-wide sequencing data in healthy individuals. The discovery gnomAD cohort contained sequencing data on 76,156 genomes and 125,748 exomes from individuals with seven ethnicity backgrounds. The three validation cohorts composed of the SG10K Project with 4810 genomes on East Asian and South Asian, the ChinaMAP project with 10,588 Chinese genomes, and the WBBC pilot project with 4480 Chinese genomes. Within each cohort, comprehensive selection criteria for various kinds of deleterious variants were instituted, including known pathogenic variants (Type 1), presumably loss-of-function changes (Type 2), predicted deleterious missense variants (Type 3), and potentially harmful in-frame INDELs (Type 4). Subsequently, carrier frequencies of the 2699 genes were calculated and ranked based on ethnicity-specific carrier rates of Type 1 to Type 4 variants. Comparison of results from different cohorts with similar ethnicity background exhibited high degree of correlation, particularly between the ChinaMAP and the WBBC cohorts (Pearson correlation coefficient R = 0.92), confirming the validity of our variant selection criteria and the overall analysis pipeline.

Estimation of carrier frequencies utilizing the gnomAD database for ACMG recommended carrier screening and Finnish disease heritage conditions in non‐Finnish European, Finnish, and Ashkenazi Jewish populations

“…The estimated GCRs by Zhu et al (2022) were, in some of the genes, quite dissimilar from this study. For instance, for GALT , the GCR was estimated to be 12.2%, whereas our estimation was 0.024% in the Finnish population (Table S6).…”

“…For instance, for GALT, the GCR was estimated to be 12.2%, whereas our estimation was 0.024% in the Finnish population (Table S6). A possible explanation for this is that GALT Duarte variant (NM_000155.2(GALT):c.-119_-116delGTCA, ClinVar variation ID: 25111) was most likely included in their study (Zhu et al, 2022), while it was excluded in our analysis.…”

“…For instance, for GALT , the GCR was estimated to be 12.2%, whereas our estimation was 0.024% in the Finnish population (Table S6). A possible explanation for this is that GALT Duarte variant (NM_000155.2( GALT ):c.‐119_‐116delGTCA, ClinVar variation ID: 25111) was most likely included in their study (Zhu et al, 2022), while it was excluded in our analysis. Most children with Duarte galactosemia do not present developmental differences when compared with controls even if exposed to dairy products (Carlock et al, 2019).…”

“…Thus, including this type of hypomorphic variant for carrier screening might not be beneficial. Another example could be MKS1 : the Finnish founder variant (NM_017777.4( MKS1 ):c.1408‐34_1408‐6del) was excluded for having conflicting classifications in ClinVar, thus causing the estimated GCR to be low (Zhu et al, 2022).…”

The effectiveness of expanded carrier screening based on next-generation sequencing for severe monogenic genetic diseases

“…Mendelian diseases may be individually rare but they are leading causes of neonatal morbidity and mortality, and in recent studies, 36.7–57.0% of critically ill infants were molecularly diagnosed with Mendelian diseases through rapid clinical exome sequencing or whole-genome sequencing [ 1 ]. Both parents or the mothers of affected individuals with autosomal recessive (AR) or X-linked recessive diseases, respectively, are carrier(s).…”