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The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. Polish National Science Centre [UMO-2016/22/E/NZ5/00270]; Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [SP1532/3-1, SP1532/4-1, SP1532/5-1]; Max Planck FoundationFoundation CELLEX; Deutsches Zentrum fur Luft-und Raumfahrt (DLR)Helmholtz AssociationGerman Aerospace Centre (DLR) [01GM1925]; Projekt DEAL Open Access funding enabled and organized by Projekt DEAL. A.J. was supported by the grant from the Polish National Science Centre UMO-2016/22/E/NZ5/00270. M.S. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SP1532/31, SP1532/4-1 and SP1532/5-1), the Max Planck Foundation and the Deutsches Zentrum fur Luft-und Raumfahrt (DLR 01GM1925).

In a patient suspected clinically to have Weaver syndrome, we ruled out mutations in EZH2 and NSD1, then identified a previously undescribed de novo mutation in EZH2's partner protein EED. Both proteins are members of the Polycomb Repressive Complex 2 that maintains gene silencing. On the basis of the similarities of the patient's phenotype to Weaver syndrome, which is caused by de novo mutations in EZH2, and on other lines of evidence including mouse Eed hypomorphs, we characterize this mutation as probably pathogenic for a Weaver-like overgrowth syndrome. This is the first report of overgrowth and related phenotypes associated with a constitutional mutation in human EED.

The Hennekam lymphangiectasia-lymphedema syndrome is a genetically heterogeneous disorder. It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases. We used homozygosity mapping and whole-exome sequencing in the original HS family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. Subsequent targeted mutation analysis of FAT4 in a cohort of 24 CCBE1 mutation-negative Hennekam syndrome patients identified homozygous or compound heterozygous mutations in four additional families. Mutations in FAT4 have been previously associated with Van Maldergem syndrome. Detailed clinical comparison between van Maldergem syndrome and Hennekam syndrome patients shows that there is a substantial overlap in phenotype, especially in facial appearance. We conclude that Hennekam syndrome can be caused by mutations in FAT4 and be allelic to Van Maldergem syndrome.

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis from deinnervated sweat glands, and delayed mental and motor development. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1), a receptor in the neurotrophin signaling pathway phosphorylated in response to nerve growth factor, are associated with this disorder. We identified six families from Northern Central Turkey with HSAN IV. We screened the NTRK1 gene for mutations in these families. Microsatellite and single nucleotide polymorphism (SNP) markers on the Affymetrix 250K chip platform were used to determine the haplotypes for three families harboring the same mutation. Screening for mutations in the NTRK1 gene demonstrated one novel frameshift mutation, two novel nonsense mutations, and three unrelated kindreds with the same splice-site mutation. Genotyping of the three families with the identical splice-site mutation revealed that they share the same haplotype. This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population.

Correction to: Journal of Human Genetics (2015) 60, 339–342; doi:10.1038/jhg.2015.26; published online 19 March 2015 Since the publication of the above article, the authors of the above paper have noticed an error in Figure 1. In the pedigree presented (Figure 1i), vertical connectors to individualsII-1 and II-2 were incorrectly omitted.

Seckel syndrome (SCKL) is a rare disease with wide phenotypic heterogeneity. A locus (SCKL1) has been identified at 3q and another (SCKL2) at 18p, both in single kindreds afflicted with the syndrome. We report here a novel locus (SCKL3) at 14q by linkage analysis in 13 Turkish families. In total, 18 affected and 10 unaffected sibs were included in the study. Of the 10 informative families, nine with parental consanguinity and one reportedly nonconsanguineous but with two affected sibs, five were indicative of linkage to the novel locus. One of those families also linked to the SCKL1 locus. A consanguineous family with one affected sib was indicative of linkage to SCKL2. The novel gene locus SCKL3 is 1.18 cM and harbors ménage a trois 1, a gene with a role in DNA repair.

The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.

Osteoectasia with hyperphosphatasia is a rare skeletal disorder, characterised by demineralisation and expansion of tubular bones and elevated serum alkaline phosphatase. We present a girl diagnosed as having osteoectasia with hyperphosphatasia who had swelling of phalanges of both hands and motor retardation. She was treated with synthetic human calcitonin. Clinical and radiological findings showed remarkable improvement after 2 years' treatment.

Seckel syndrome (SCKL) is a rare disease with wide phenotypic heterogeneity. A locus (SCKL1) has been identified at 3q and another (SCKL2) at 18p, both in single kindreds afflicted with the syndrome. We report here a novel locus (SCKL3) at 14q by linkage analysis in 13 Turkish families. In total, 18 affected and 10 unaffected sibs were included in the study. Of the 10 informative families, nine with parental consanguinity and one reportedly nonconsanguineous but with two affected sibs, five were indicative of linkage to the novel locus. One of those families also linked to the SCKL1 locus. A consanguineous family with one affected sib was indicative of linkage to SCKL2. The novel gene locus SCKL3 is 1.18 cM and harbors menage a trois 1, a gene with a role in DNA repair.