TY - JOUR
T1 - A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy
AU - Al-Thihli, Khalid
AU - Ebrahim, Hatim
AU - Hughes, Derralynn A.
AU - Patel, Millan
AU - Tipple, Marion
AU - Salvarinova, Ramona
AU - Gardiner, Jane
AU - Vallance, Hilary
AU - Waters, Paula J.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, and largely caused by mutations in genes encoding sarcomere proteins. However, GLA mutations causing Fabry disease, an X-linked lysosomal storage disorder, may also present with isolated HCM. As HCM genetic testing panels are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a 10-year-old girl with isolated HCM who, on testing with a HCM multi-gene panel, was found to carry a maternally inherited p.W24R variant in GLA. Attempts to evaluate the significance of this variant, by direct biochemical testing of patient specimens, gave inconclusive results. Subsequent in vitro protein expression studies suggested that the variant is unlikely to be pathogenic. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether GLA sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.
AB - Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, and largely caused by mutations in genes encoding sarcomere proteins. However, GLA mutations causing Fabry disease, an X-linked lysosomal storage disorder, may also present with isolated HCM. As HCM genetic testing panels are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a 10-year-old girl with isolated HCM who, on testing with a HCM multi-gene panel, was found to carry a maternally inherited p.W24R variant in GLA. Attempts to evaluate the significance of this variant, by direct biochemical testing of patient specimens, gave inconclusive results. Subsequent in vitro protein expression studies suggested that the variant is unlikely to be pathogenic. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether GLA sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.
KW - Fabry disease
KW - GLA
KW - Hypertrophic cardiomyopathy
KW - Variant of unknown significance
KW - α-Galactosidase A
UR - http://www.scopus.com/inward/record.url?scp=84858279462&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84858279462&partnerID=8YFLogxK
U2 - 10.1016/j.gene.2012.01.056
DO - 10.1016/j.gene.2012.01.056
M3 - Article
C2 - 22336178
AN - SCOPUS:84858279462
SN - 0378-1119
VL - 497
SP - 320
EP - 322
JO - Gene
JF - Gene
IS - 2
ER -