Nonsyndromic cleft lip with or without palate (CL/P) is thought to be caused by the interplay of genetic and environmental factors, and this has thus hindered the process of identifying genetic causative factors. Numerous studies in the past decade have implicated IRF6 in CL/P, but this has not often been replicated in other populations. In specific, the only etiologic single-nucleotide polymorphism (SNP) identified in the IRF6 locus (rs642961) has recently been shown not to be associated with CL/P in diverse populations. We therefore used a genewide tagging SNP (tagSNP) haplotyping approach (including rs642961 as a tagSNP) to detect all potential risk-conferring haplotypes and combined this with detailed subphenotyping of CL/P cases (N = 150) according to severity. We observed a significant overrepresentation of a tagSNP haplotype carrying the rs642961 risk allele in the most severe subphenotype of CL/P (complete bilateral CL/P; P = 0.008, odds ratio = 4.97, 95% confidence interval = 1.33 to 18.46). It was recently shown that >80% of IRF6 mutations in syndromic CL/P occur on the same haplotype background. We therefore suggest that IRF6 is a marker of CL/P severity.

Nonsyndromic oral clefting (NSOC) is although one of the most common congenital disorders worldwide, its underlying molecular basis remains elusive. This process has been hindered by the overwhelmingly high level of heterogeneity observed. Given that hitherto multiple loci and genes have been associated with NSOC, and that complex diseases are usually polygenic and show a considerable level of missing heritability, we used a systems genetics approach to reconstruct the NSOC network by integrating human-based physical and regulatory interactome with whole-transcriptome microarray data. We show that the network component contains 53% (23/43) of the curated NSOC-implicated gene set and displays a highly significant propinquity (P < 0.0001) between genes implicated at the genomic level and those differentially expressed at the transcriptome level. In addition, we identified bona fide candidate genes based on topological features and dysregulation (e.g. ANGPTL4), and similarly prioritised genes at GWA loci (e.g. MYC and CREBBP), thus providing further insight into the underlying heterogeneity of NSOC. Gene ontology analysis results were consistent with the NSOC network being associated with embryonic organ morphogenesis and also hinted at an aetiological overlap between NSOC and cancer. We therefore recommend this approach to be applied to other heterogeneous complex diseases to not only provide a molecular framework to unify genes which may seem as disparate entities linked to the same disease, but to also predict and prioritise candidate genes for further validation, thus addressing the missing heritability.

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It has been established that the male-specific region of the Y chromosome (MSY) carries genes that contribute to spermatogenesis and male fertility. In the past decades, there have been numerous attempts to identify the genes that are responsible for spermatogenesis (Tyler-Smith & Krausz, 2009). Identifying genetic variation (i.e. causative variants) in MSY genes that could be potentially used as possible markers for diagnosis of male infertility has proved to be challenging. It has been reported that 2 to 3% of human males are infertile due to defects in spermatogenesis, primarily because of oligozoospermia or azoospermia (Hull et al., 1985). MSY abnormality, mainly in the form of microdeletions, can be found in about 10% of such males (Choi et al., 2012; Umeno et al., 2006). The first search for candidate genes began in 1976 where cytogenetically visible Yq deletions were identified in six patients with azoospermia (Tiepolo & Zuffardi, 1976). Based on molecular genetic techniques, in 1996,

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