Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.
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.
Rankin
Julia
J
Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. julia.rankin@rdeft.nhs.uk
Auer-Grumbach
Michaela
M
Bagg
Warwick
W
Colclough
Kevin
K
Nguyen
Thuy Duong
TD
Fenton-May
Jane
J
Hattersley
Andrew
A
Hudson
Judith
J
Jardine
Philip
P
Josifova
Dragana
D
Longman
Cheryl
C
McWilliam
Robert
R
Owen
Katharine
K
Walker
Mark
M
Wehnert
Manfred
M
Ellard
Sian
S
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
D034904:Lamin Type A; D001120:Arginine; D003545:Cysteine