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3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD). Design Case series. Participants A total of 562 patients diagnosed with IRD. Methods We performed a direct comparative analysis of current molecular diagnostics with WGS. We retrospectively reviewed the findings from a diagnostic NGS DNA test for 562 patients with IRD. A subset of 46 of 562 patients (encompassing potential clinical outcomes of diagnostic analysis) also underwent WGS, and we compared mutation detection rates and molecular diagnostic yields. In addition, we compared the sensitivity and specificity of the 2 techniques to identify known single nucleotide variants (SNVs) using 6 control samples with publically available genotype data. Main Outcome Measures Diagnostic yield of genomic testing. Results Across known disease-causing genes, targeted NGS and WGS achieved similar levels of sensitivity and specificity for SNV detection. However, WGS also identified 14 clinically relevant genetic variants through WGS that had not been identified by NGS diagnostic testing for the 46 individuals with IRD. These variants included large deletions and variants in noncoding regions of the genome. Identification of these variants confirmed a molecular diagnosis of IRD for 11 of the 33 individuals referred for WGS who had not obtained a molecular diagnosis through targeted NGS testing. Weighted estimates, accounting for population structure, suggest that WGS methods could result in an overall 29% (95% confidence interval, 15–45) uplift in diagnostic yield. Conclusions We show that WGS methods can detect disease-causing genetic variants missed by current NGS diagnostic methodologies for IRD and thereby demonstrate the clinical utility and additional value of WGS. [ABSTRACT FROM AUTHOR]

Abstract: Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene. [Copyright &y& Elsevier]

Pterygium syndromes are complex congenital disorders that encompass several distinct clinical conditions characterized by multiple skin webs affecting the flexural surfaces often accompanied by craniofacial anomalies. In severe forms, such as in the autosomal-recessive Bartsocas-Papas syndrome, early lethality is common, complicating the identification of causative mutations. Using exome sequencing in a consanguineous family, we identified the homozygous mutation c.1127C>A in exon 7 of RIPK4 that resulted in the introduction of the nonsense mutation p.Ser376X into the encoded ankyrin repeat-containing kinase, a protein that is essential for keratinocyte differentiation. Subsequently, we identified a second mutation in exon 2 of RIPK4 (c.242T>A) that resulted in the missense variant p.Ile81Asn in the kinase domain of the protein. We have further demonstrated that RIPK4 is a direct transcriptional target of the protein p63, a master regulator of stratified epithelial development, which acts as a nodal point in the cascade of molecular events that prevent pterygium syndromes. [ABSTRACT FROM AUTHOR]

3-M syndrome, a primordial growth disorder, is associated with mutations in CUL7 and OBSL1. Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome. CCDC8 is a widely expressed gene that is transcriptionally associated to CUL7 and OBSL1, and coimmunoprecipitation indicates a physical interaction between CCDC8 and OBSL1 but not CUL7. We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth. [Copyright &y& Elsevier]

Amelogenesis imperfecta (AI) describes a clinically and genetically heterogeneous group of disorders of biomineralization resulting from failure of normal enamel formation. AI is found as an isolated entity or as part of a syndrome, and an autosomal-recessive syndrome associating AI and gingival hyperplasia was recently reported. Using whole-exome sequencing, we identified a homozygous nonsense mutation in exon 2 of FAM20A that was not present in the Single Nucleotide Polymorphism database (dbSNP), the 1000 Genomes database, or the Centre d''Etude du Polymorphisme Humain (CEPH) Diversity Panel. Expression analyses indicated that Fam20a is expressed in ameloblasts and gingivae, providing biological plausibility for mutations in FAM20A underlying the pathogenesis of this syndrome. [Copyright &y& Elsevier]

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a “pseudo-TORCH” syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa is a genetically heterogeneous group of inherited ocular disorders characterized by progressive photoreceptor cell loss, night blindness, constriction of the visual field, and progressive visual disability. Homozygosity mapping and gene expression studies identified a 2 exon gene, C2ORF71. The encoded protein has no homologs and is highly expressed in the eye, where it is specifically expressed in photoreceptor cells. Two mutations were found in C2ORF71 in human RP patients: A nonsense mutation (p.W253X) in the first exon is likely to be a null allele; the second, a missense mutation (p.I201F) within a highly conserved region of the protein, leads to proteosomal degradation. Bioinformatic and functional studies identified and validated sites of lipid modification within the first three amino acids of the C2ORF71 protein. Using morpholino oligonucleotides to knockdown c2orf71 expression in zebrafish results in visual defects, confirming that C2ORF71 plays an important role in the development of normal vision. Finally, localization of C2ORF71 to primary cilia in cultured cells suggests that the protein is likely to localize to the connecting cilium or outer segment of photoreceptor cells. [ABSTRACT FROM AUTHOR]