■耳廓椎体频谱(OAVS)包括来自第一和第二咽弓的衍生物的各种异常,包括大口,半面微缩,小颌畸形,耳前标记,眼和椎骨异常。我们介绍了一个大型的三代家族的遗传发现,该家族具有多个成员,耳前标记和单-或双侧下垂遵循常染色体显性分离模式。
■我们为先证者生成了全基因组测序数据,受影响的父母和未受影响的父辈祖父母,然后对23个家族成员进行Sanger测序,获得前10个候选基因:KCND2,PDGFRA,CASP9,NCOA3,WNT10A,SIX1,MTF1,KDR/VEGFR2,LRRK1,和TRIM2。我们进行了基于父母和兄弟姐妹的传播不平衡测试和负担分析,以探索候选基因突变的分离和负担。生物信息学分析研究了基因与异常表型之间的生物学联系。
■总的来说,SIX1,KDR/VEGFR2中的罕见错义突变,PDGFRA显示出与该家族中OAV表型分离的最佳证据。当考虑对3种OAVS表型中的任何一种的影响作为结果时,parent-TDTs和sib-TDTs(未调整的p值)发现SIX1(p=0.025,p=0.052),其次是PDGFRA(p=0.180,p=0.069)和KDR/VEGFR2(p=0.180,p=0.069)在该家族中具有最强的关联。通过惩罚线性混合模型的负担分析确定SIX1(RC=0.87)和PDGFRA(RC=0.98)与OAVS严重程度具有最强的关联。使用表型特异性ogfrautcomes,同胞-TDT识别之间的关联(1)SIX1与单-或双侧下垂(p=0.049)和耳标(p=0.01),(2)PDGFRA和KDR/VEGFR2具有耳标(均p<0.01)。
■我们的研究报告了一个大家族的基因组发现,该家族的多个个体受到常染色体显性遗传的OAVS表型的影响。我们的发现缩小到三个潜在的候选基因,SIX1,PDGFRA,和KDR/VEGFR2。其中,SIX1先前与OAVS耳朵畸形有关,并且在耳朵发育过程中与EYA1共表达。尝试加强表型OAVS的基因型-表型相关性对于发现导致这种复杂而繁重的疾病的病因因素以及家庭咨询和预防工作至关重要。
UNASSIGNED: Oculoauriculovertebral Spectrum (OAVS) encompasses a wide variety of anomalies on derivatives from the first and second pharyngeal arches including
macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular and vertebral anomalies. We present the genetic findings of a large three-generation family with multiple members affected with
macrostomia, preauricular tags and uni- or bilateral ptosis following an autosomal dominant segregation pattern.
UNASSIGNED: We generated whole genome sequencing data for the proband, affected parent and unaffected paternal grandparent followed by Sanger sequencing on 23 family members for the top 10 candidate genes: KCND2, PDGFRA, CASP9, NCOA3, WNT10A, SIX1, MTF1, KDR/VEGFR2, LRRK1, and TRIM2. We performed parent and sibling-based transmission disequilibrium tests and burden analysis to explore segregation and burden of candidate gene mutations. Bioinformatic analyses investigated the biological connection between genes and the abnormal phenotypes.
UNASSIGNED: Overall, rare missense mutations in SIX1, KDR/VEGFR2, and PDGFRA showed the best evidence of segregation with the OAV phenotypes in this family. When considering affection with any of the 3 OAVS phenotypes as an outcome, parent-TDTs and sib-TDTs (unadjusted p-values) found that SIX1 (p=0.025, p=0.052), followed by PDGFRA (p=0.180, p=0.069) and KDR/VEGFR2 (p=0.180, p=0.069) have the strongest associations in this family. Burden analysis via a penalized linear mixed model identified SIX1 (RC=0.87) and PDGFRA (RC=0.98) as having the strongest association with OAVS severity. Using phenotype-specific ogfrautcomes, sib-TDTs identified associations between (1) SIX1 with uni- or bilateral ptosis (p=0.049) and ear tags (p=0.01), (2) PDGFRA and KDR/VEGFR2 with ear tags (both p<0.01).
UNASSIGNED: Our study reports the genomic findings of a large family with multiple individuals affected with OAVS phenotypes with autosomal dominant inheritance. Our findings narrow down to three potential candidate genes, SIX1, PDGFRA, and KDR/VEGFR2. Among these, SIX1 has been previously associated with OAVS ear malformations and it is co-expressed with EYA1 during ear development. Attempts to strengthen the genotype-phenotype co-relation underlying the OAVS of phenotypes are essential to discover the etiological factors leading to this complex and burdensome condition as well as for family counseling and prevention efforts.