Mutations in MEOX1, Encoding Mesenchyme Homeobox 1, Cause Klippel-Feil Anomaly.
ABSTRACT Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript. Direct sequencing of this gene in two siblings from another consanguineous family affected by isolated KFS uncovered another homozygous truncating (nonsense) MEOX1 mutation that also leads to complete degradation of the transcript. This gene encodes a transcription factor with a well-established and nonredundant role in somite development, and homozygous null alleles of Meox1 in mice have a cervical skeletal defect that is remarkably similar to the one we observe in human individuals with MEOX1 mutations. Our data strongly suggest that KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.
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ABSTRACT: Autozygosity, or the inheritance of two copies of an ancestral allele, has the potential to not only reveal phenotypes caused by biallelic mutations in autosomal recessive genes, but to also facilitate the mapping of such mutations by flagging the surrounding haplotypes as tractable runs of homozygosity (ROH), a process known as autozygosity mapping. Since SNPs replaced microsatellites as markers for the purpose of genomewide identification of ROH, autozygosity mapping of Mendelian genes has witnessed a significant acceleration. Historically, successful mapping traditionally required favorable family structure that permits the identification of an autozygous interval that is amenable to candidate gene selection and confirmation by Sanger sequencing. This requirement presented a major bottleneck that hindered the utilization of simplex cases and many multiplex families with autosomal recessive phenotypes. However, the advent of next-generation sequencing that enables massively parallel sequencing of DNA has largely bypassed this bottleneck and thus ushered in an era of unprecedented pace of Mendelian disease gene discovery. The ability to identify a single causal mutation among a massive number of variants that are uncovered by next-generation sequencing can be challenging, but applying autozygosity as a filter can greatly enhance the enrichment process and its throughput. This review will discuss the power of combining the best of both techniques in the mapping of recessive disease genes and offer some tips to troubleshoot potential limitations.Human Genetics 08/2013; 132(11). DOI:10.1007/s00439-013-1344-x · 4.52 Impact Factor
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ABSTRACT: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans.BMC Genetics 09/2013; 14(1):95. DOI:10.1186/1471-2156-14-95 · 2.36 Impact Factor
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ABSTRACT: A 4-year-old girl was referred for recurrent neck pain. On examination, she was noted to have a short neck with very limited range of motion and a low-set posterior hairline. Suspecting Klippel-Feil Syndrome (KFS), X-rays (figure 1A and B) and CT (figure 1C and D) with three-dimensional reconstruction (see online supplementary video 1) were performed and a complex malformation of the cervical spine and craniocervical junction was detected.Archives of Disease in Childhood 11/2013; 99(3). DOI:10.1136/archdischild-2013-305203 · 2.91 Impact Factor