(mentions CMT 2) Extreme phenotypic diversity and nonpenetrance in families with

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Am J Med Genet A. 2008 May 13

Extreme phenotypic diversity and nonpenetrance in families with the

LMNA gene mutation R644C.

Rankin J, Auer-Grumbach M, Bagg W, Colclough K, Duong NT, Fenton-May

J, Hattersley A, Hudson J, Jardine P, Josifova D, Longman C,

Mc R, Owen K, M, Wehnert M, Ellard S.

Department of Clinical Genetics, Royal Devon and Exeter NHS

Foundation Trust, Exeter, UK.

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.