Variantes raras encontradas en familias múltiples con hendiduras orofaciales: ¿Ampliar el fenotipo hace alguna diferencia??

Exome sequencing (ES) is now a relatively straightforward process to
identify causal variants in Mendelian disorders. Sin embargo, the same is not
true for ES in families where the inheritance patterns are less clear, y
a complex etiology is suspected. Hendiduras orofaciales (OFC) are highly
heritable birth defects with both Mendelian and complex etiologies. El
phenotypic spectrum of OFCs may include overt clefts and several
subclinical phenotypes, such as discontinuities in the orbicularis oris
muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI),
microform clefts or bifid uvulas. We hypothesize that expanding the OFC
phenotype to include these phenotypes can clarify inheritance patterns in
multiplex families, making them appear more Mendelian. We performed exome
sequencing to find rare, likely causal genetic variants in 31 multiplex OFC
familias, which included families with multiple individuals with OFCs and
individuals with subclinical phenotypes. We identified likely causal
variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families.
Although we did not find clear evidence supporting the subclinical
phenotype hypothesis, our findings support a role for rare variants in the
etiology of OFCs.