{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:44:51Z","timestamp":1791121491188,"version":"4.1.0"},"reference-count":30,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2010,2,13]]},"published-print":{"date-parts":[[2010,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Limb development is a complex process requiring proper spatio-temporal expression of a network of limb specific morphogens. <jats:italic>Grem1<\/jats:italic> and <jats:italic>Fmn1<\/jats:italic> play an important role in mouse and chick limb development. The mouse <jats:italic>limb deformity<\/jats:italic> (<jats:italic>ld<\/jats:italic>) phenotype with digit reduction, syndactyly, radio-ulnar synostosis, variable renal defects and absent fibulae is caused by loss of <jats:italic>Grem1<\/jats:italic> function. This could be due to either coding <jats:italic>Grem1<\/jats:italic> homozygous mutations or homozygous deletions of the neighbouring <jats:italic>Fmn1<\/jats:italic> gene, which also removes limb specific regulatory sequences of <jats:italic>Grem1<\/jats:italic>. Recent studies reinforce the hypothesis that a loss of <jats:italic>Fmn1<\/jats:italic> protein could also contribute to the observed <jats:italic>ld<\/jats:italic> anomalies. In addition, an over-expression of <jats:italic>Grem1<\/jats:italic> in developing chick limbs represses the programmed cell death in the interdigital mesenchyme, resulting in interdigital webbing and truncation of distal cartilage elements.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Aims\/Results<\/jats:title>\n                  <jats:p>For the first time, chromosomal imbalances in the <jats:italic>GREM1<\/jats:italic> \n                     <jats:italic>FMN1<\/jats:italic> region in individuals with limb defects are reported here. A 263\u2005Kb homozygous deletion of <jats:italic>FMN1<\/jats:italic> was associated with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects, features identical to <jats:italic>ld<\/jats:italic> mice. A 1.7\u2005Mb duplication encompassing both the <jats:italic>GREM1<\/jats:italic> and <jats:italic>FMN1<\/jats:italic> genes was detected in a patient with isolated Cenani\u2013Lenz-like oligosyndactyly of the hands, resembling the transgenic chick wings in which <jats:italic>Grem1<\/jats:italic> was over-expressed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The phenotypes of these two patients represent new entities\/syndromes within the Cenani\u2013Lenz clinical spectrum: (1) an autosomal recessive oligosyndactyly, radio-ulnar synostosis, hearing loss and renal defect syndrome; and (2) an autosomal dominant Cenani\u2013Lenz-like non-syndromic oligosyndactyly.<\/jats:p>\n               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