TY - JOUR
T1 - Novel no-stop FLNA mutation causes multi-organ involvement in males
AU - Oegema, Renske
AU - Hulst, Jessie M.
AU - Theuns-Valks, Sabine D.M.
AU - van Unen, Leontine M.A.
AU - Schot, Rachel
AU - Mancini, Grazia M.S.
AU - Schipper, Marguerite E.I.
AU - de Wit, Marie C.Y.
AU - Sibbles, Barbara J.
AU - de Coo, Irenaeus F.M.
AU - Nanninga, Veerle
AU - Hofstra, Robert M.W.
AU - Halley, Dicky J.J.
AU - Brooks, Alice S.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.
AB - Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.
KW - Congenital short bowel
KW - Filamin A
KW - Intestinal malrotation
KW - Periventricular nodular heterotopia
UR - http://www.scopus.com/inward/record.url?scp=84881663552&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.36109
DO - 10.1002/ajmg.a.36109
M3 - Article
C2 - 23873601
AN - SCOPUS:84881663552
SN - 1552-4825
VL - 161
SP - 2376
EP - 2384
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
ER -