TY - JOUR

T1 - X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

AU - Møller, R S

AU - Jensen, L R

AU - Maas, S M

AU - Filmus, J

AU - Capurro, M

AU - Hansen, Claus

AU - Marcelis, C L M

AU - Ravn, K

AU - Andrieux, J

AU - Mathieu, M

AU - Kirchhoff, M

AU - Rødningen, O K

AU - de Leeuw, N

AU - Yntema, H G

AU - Froyen, G

AU - Vandewalle, J

AU - Ballon, K

AU - Klopocki, E

AU - Joss, S

AU - Tolmie, J

AU - Knegt, A C

AU - Lund, A M

AU - Hjalgrim, H

AU - Kuss, A W

AU - Tommerup, N

AU - Ullmann, R

AU - de Brouwer, A P M

AU - Strømme, P

AU - Kjaergaard, S

AU - Tümer, Z

AU - Kleefstra, T

PY - 2014

Y1 - 2014

N2 - Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

AB - Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

KW - Abnormalities, Multiple

KW - Adult

KW - Animals

KW - Blepharoptosis

KW - Body Height

KW - Child

KW - Chromosome Duplication

KW - Cleft Palate

KW - Female

KW - Fingers

KW - Genetic Diseases, X-Linked

KW - Humans

KW - Intellectual Disability

KW - Karyotyping

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Microcephaly

KW - Syndrome

U2 - 10.1007/s00439-013-1403-3

DO - 10.1007/s00439-013-1403-3

M3 - Journal article

C2 - 24326587

VL - 133

SP - 625

EP - 638

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 5

ER -