Recurrent IGFALS gene mutations p.E35Gfs*17 and p.[L409F;A475V]: hot spot or founder effect?.

SCAGLIA P ; SALA A; BERGADA I; BRASLAVSKY D; ANA KESELMAN, ANGELA ESPÍNOLA CASTRO, SABINA DOMENÉ, HÉCTOR JASPER,; CORACH D; DOMENÉ H

Barcelona

Congreso; 54th Annual Meeting of the European Society of Paediatric Endocrinology; 2015

European Society of Paediatric Endocrinology

Background:Some IGFALSvariants have been reported in more than one ALS deficient family, raising thequestion whether they originated from a single common ancestor allele (foundereffect) or alternatively, as independent mutational events (hot spot). The factthat c.103dupG (p.E35Gfs*17) is located in a stretch of 5 consecutive guanineresidues, where both G-duplication and deletion have been described in familiesfrom different countries, led us to speculate that this region could be a hotspot. In contrast, c.[1225C>T;1424C>T] (p.[L409F;A475V]) variants, bothpresent in the same allele in two unrelated families, could result from afounder effect.Objectiveand hypotheses: To test the hypothesis of a foundereffect vs hot spot by studying polymorphic variants surrounding IGFALS gene and uniparental lineagemarkers in families harboring the c.103dupG and c.[1225C>T;1424C>T]variants.Method:We sequenced the whole IGFALS gene and characterized 2 STRs flanking IGFALS gene locus in 2 unrelated families harboring thec.[1225C>T;1424C>T] variants and in 4 unrelated families carriers ofc.103dupG. Nine informative SNPs and 2 STRs (D16S3435 and D16S3024) were usedto define the specific haplotype associated to the mutation. In addition, patriand matrilineal lineages were analyzed by means of 23 Y-STRs typing andmtDNA-D-Loop sequencing.Results:Four families carrying the c.103dupG variantpresented the microhaplotype (CA)12/gtcggtgcc/(CA)21 while the 2 familiescarriers of c.[1225C>T;1424C>T] variants presented a differentmicrohaplotype (CA)15/acgaaccgt/(CA)22 or (CA)23. None of these particularmicrohaplotypes were found in any of the wild type alleles. Phylogeneticanalysis revealed that all male lineages can be attributed to European or Eurasianhaplogroups (50% E1b1b; 33% R1b and 17% Q) while mtDNA lineage belonged toNative American (55.5%), African (22%) and European (22%) hgs.Conclusion:Even if the number of families studied is limited,our findings support the hypothesis that each variant, c.103dupG andc.[1225C>T;1424C>T], originated independently from a single commonancestor allele.