The Ser14Phe, Arg342His, and Arg488Met variants were frequent in Africa and occasionally observed in the Middle East and Central Asia, but were completely missing in Europe and America.
FA gene variants were frequent in our t-MN patients, with 6 out of 37 patients (16%) carriers of at least one genomic variant, with similar prevalence in t-MN secondary to lymphoproliferative diseases versus solid tumors (4 out of 19 vs 2 out of 18, respectively).
Reviewer #3 minor comments: 1) Introduction: this sentence gives the impression that intermediate frequency variants are frequent in the genome.
This methodology is suitable for settings where the risk effect of these polymorphisms is relatively low but the pathogenic allele variants are frequent in the overall population.
The authors [ 5] concluded that cis-acting regulatory variants are frequent and could be used to clarify the genetic risk of complex disorders.
For nonsyndromic (NS) HI, causal variants in ~80 genes have been identified and some of these variants are frequent in individuals with NSHI in particular populations, for example, variants in GJB2.
There are several reports of β-thalassemia variants in patients from Northern Europe with no known ancestry in regions where thalassemia is endemic, but so far it cannot be ruled out that these variants might have been introduced by recent migrations from regions where β-thalassemia variants are frequent.
Prompted by these findings, the data originally suggesting that the 295C variant was frequent in the Dutch population (7) were reassessed, and could not be replicated (E. de Graaff, personal communication).
In general there are two possibilities: (i) a sequence variant is frequent, then deviations of the allele count across the available pools are very likely; (ii) a sequence variant is rare, then it is unlikely, that the variant appears in all tested pools.
Variants were most frequent in exon 3 (Table 2), and no variation was found in exons 1, 2, 6, 8 11, 16 20, 22, and 24.
Variants were most frequent in exon 2 (7 variants found in 6 patients), followed by exons 11 and 12. Besides, several polymorphisms were detected, including c.61T>C (p.W21R), c.154G>T (p.andS), and c.2101C>T (p.P701S), respectively (Table S5).
