title: Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.
abstract: Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.
authors.affiliation: Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. julia.rankin@rdeft.nhs.uk
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Warwick
authors.initials: W
authors.lastname: Bagg
authors.forename: Kevin
authors.initials: K
authors.lastname: Colclough
authors.forename: Thuy Duong
authors.initials: TD
authors.lastname: Nguyen
authors.forename: Jane
authors.initials: J
authors.lastname: Fenton-May
authors.forename: Andrew
authors.initials: A
authors.lastname: Hattersley
authors.forename: Judith
authors.initials: J
authors.lastname: Hudson
authors.forename: Philip
authors.initials: P
authors.lastname: Jardine
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Robert
authors.initials: R
authors.lastname: McWilliam
authors.forename: Katharine
authors.initials: K
authors.lastname: Owen
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D002648:Child; D003545:Cysteine / Q000235:genetics; D005260:Female; D030342:Genetic Diseases, Inborn; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D019683:Penetrance; D010641:Phenotype
chemical_list: D034904:Lamin Type A; D001120:Arginine; D003545:Cysteine