We were unable to identify any previous published reports of segregation ratios for EVA.
Our segregation ratios for M1 families confirm the pathogenic contribution of detected mono-allelic mutations to EVA and support the hypothesis that EVA is inherited as a mono- or digenic recessive trait in those families. Although our M1 segregation ratio was greater than the expected Mendelian result of 0.25, it was similar to the ratio observed among the M2 families in whom EVA was inherited as a monogenic autosomal recessive trait. The lack of a significant difference between M1 and M2 ratios might be due to the small number of families, especially M1 families. However, the high M1 ratio seems unlikely to reflect dominant inheritance because we have not observed vertical transmission of EVA in M0 or M1 families. The ratios for all of the genotype groups likely reflect an ascertainment bias for multiplex sibships in the families referred to our study.
If the hypofunctional alleles p.R776C and c.-3-2A>G are considered to be non-pathogenic,19 22
there is no longer evidence for digenic or complex inheritance among our M1 families. The lack of discordant segregation of EVA with SLC26A4
linked STR markers in M1 families is thus consistent with the hypothesis of autosomal recessive inheritance of bi-allelic mutations of SLC26A4
, although we cannot exclude the possibility of digenic inheritance in M1 families.
Although we were unable to find evidence of pathogenic copy number variations or non-coding sequence mutations, they may reside elsewhere in intronic or regulatory regions that we did not evaluate. Occult mutant alleles of SLC26A4
would be predicted to encode some residual pendrin since the thyroid and auditory phenotypes in M1 patients are generally less severe than in M2 patients. Abnormal perchlorate discharge results are observed almost exclusively among M2 patients,7 18
unilateral EVA is more prevalent among M1 patients whereas EVA is almost always bilateral in M2 patients, and M1 patients tend to have better hearing thresholds than M2 patients.7 11 23
Given the probable influence of ascertainment bias on our segregation ratios, the actual M0 ratio may be closer to zero than our observed ratio of approximately 0.1. This low ratio and discordant segregation of EVA with SLC26A4 in eight of 24 M0 families are consistent with a non-genetic or complex aetiology, or aetiologic heterogeneity that may include Mendelian inheritance in some families. However, we did not detect phenotypic evidence for etiologic heterogeneity among the M0 group since there was no significant difference in hearing thresholds between familial and sporadic patients (not shown).
The twin pairs in our M0 cohort raise the possibility of a causal relationship or a shared aetiology with twinning such as that described for other phenotypes including Beckwith–Wiedemann24 25
and Goldenhar syndromes26
However, we identified no patterns among the M0 twin pregnancies to indicate a causal relationship between twinning and EVA (supplemental table S2
This is the first study to estimate the recurrence risk of EVA, which will be useful for counselling families segregating EVA and one or no detectable mutations of SLC26A4. Families with EVA and one detectable mutation of SLC26A4 seem likely to be segregating EVA as a trait caused by that mutation in combination with a second occult mutant allele of SLC26A4 or another autosomal gene. In contrast, EVA appears to be a non-genetic or complex trait with a significantly lower recurrence rate in families with no detectable SLC26A4 mutations. The discovery of a source of occult mutations in families with non-diagnostic SLC26A4 genotypes could clarify the aetiology and recurrence risk of EVA in those families.
- We calculated segregation ratios and analysed the segregation of SLC26A4 linked markers in enlargement of the vestibular aqueduct (EVA) families with non-diagnostic SLC26A4 genotypes.
- Our results support the hypothesis of a second, undetected SLC26A4 mutation in M1 patients, whereas EVA appears to be caused by mutations in other genes, non-genetic factors, or both as a complex trait in M0 patients.
- These results will be helpful for recurrence risk counselling of EVA families with non-diagnostic SLC26A4 genotypes.