A cohort study of recurrence patterns among more than 54 000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance

Abstract

Objectives To determine if the anatomical severity of oral clefting affects familial recurrence in a large population based sample. To provide reliable recurrence risk estimates for oral cleft for first-, second-, and third-degree relatives. Design Population based cohort study Setting Denmark Participants 6,776 individuals affected with an oral cleft born from 1952 to 2005 and 54,229 relatives. Main outcome measures Recurrence risk estimates for oral cleft for first-, second-, and third-degree relatives and stratification by severity, specificity, parent of origin effect, and family size for first-degree relatives. Results For cleft lip and palate probands we observed recurrence risks for first-, second-, and third degree relatives of respectively 3.5% (95% confidence interval 3.1% to 4.0%), 0.8 % (0.6% to 1.0%), and 0.6% (0.4% to 0.8%). Individuals affected by the most severe oral cleft had a significantly higher recurrence risk among both offspring and siblings, e.g. the recurrence risk for siblings of a proband with isolated bilateral cleft lip with cleft palate was 4.6% (3.2 to 6.1) versus 2.5% (1.8 to 3.2) for a proband born with a unilateral defect. Conclusions Anatomical severity does have an effect on recurrence in first-degree relatives and the type of cleft is predictive of the recurrence type. Highly reliable estimates of recurrence have been provided for first cousins in addition to more accurate estimates for first and second degree relatives. These results and the majority of prior data continue to support a multifactorial threshold model of inheritance.

8 Epidemiology of Cleft Lip and Palate

“…The risk of CL/P and CP has been reported to be increased in the first-, second-, and third-degree relatives and the identical twins of individuals with CL/P and CP, with even nonsyndromic cases of CL/P exhibiting evidence of genetic components [58][59][60][61]. However, few cases demonstrate true Mendelian inheritance patterns [62].…”

Investigação do papel de SNVs (single nucleotide variants) na etiologia da fissura lábio-palatina não sindrômica

“…Esses dados, juntamente com fatores como altas taxas de agregação familiar, altas estimativas de herdabilidade (variando de 45 a 85% no Brasil) e elevadas taxas de concordância de gêmeos monozigóticos (40--60%) versus dizigóticos (3--5%), evidenciam um forte componente genético na etiologia da FL/P NS CHRISTENSEN & FOGH--ANDERSEN, 1993;HECHT et al, 1991;). …”

“…O principal gene candidato da região é o VAX1, um fator de transcrição aparentemente envolvido no desenvolvimento do prosencéfalo, e está localizado a 53kb da região de associação . Camundongos homozigotos para mutações em Vax1 apresentam malformações craniofaciais, incluindo fissura de palato (HALLONET et al, 1999).…”

“…Isso pode ter sido devido à significância marginal dos eQTLs escolhidos para estudo de associação caso--controle (FDR>42.5%). Além disso, a casuística utilizada (N=46) para o mapeamento é bastante pequena em comparação com estudos de eQTLs que vêm sendo realizados (GRUNDBERG et al, 2012). Em estudos com baixo poder, os eQTLs detectados são aqueles de maior efeito, e esses geralmente são compartilhados entre diferentes tecidos (NICA et al, 2011;GRUNDBERG et al, 2012).…”

Variantes genéticas de risco às fissuras orofaciais

“…Another evidence for this genetic role comes from recurrence risk, which is 20-30 times higher in 1 st -degree relatives of affected individuals than the population risk (Sivertsen et al, 2008;Grosen et al, 2010). Extensive research has been conducted in order to uncover the genetic basis of NSCL/P, and several susceptibility loci have emerged in the recent years.…”