The duplication 17p13.3 phenotype

Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes

Cynthia J. Curry, Jill A. Rosenfeld, Erica Grant, Karen W. Gripp, Carol Anderson, Arthur S. Aylsworth, Taha Ben Saad, Victor V. Chizhikov, Giedre Dybose, Christina Fagerberg, Michelle Falco, Christina Fels, Marco Fichera, Jesper Graakjaer, Donatella Greco, Jennifer Hair, Elizabeth Hopkins, Marlene Huggins, Roger Ladda, Chumei Li & 22 others John Moeschler, Malgorzata J M Nowaczyk, Jillian R. Ozmore, Santina Reitano, Corrado Romano, Laura Roos, Rhonda E. Schnur, Susan Sell, Pim Suwannarat, Dea Svaneby, Marta Szybowska, Mark Tarnopolsky, Raymond Tervo, Anne Tsai, Megan Tucker, Stephanie Vallee, Ferrin C. Wheeler, Dina J. Zand, A. James Barkovich, Swaroop Aradhya, Lisa G. Shaffer, William B. Dobyns

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

Original languageEnglish (US)
Pages (from-to)1833-1852
Number of pages20
JournalAmerican Journal of Medical Genetics, Part A
Volume161
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Phenotype
Brain
Connective Tissue
Foot
Classical Lissencephalies and Subcortical Band Heterotopias
Hand
Genes
Bone and Bones
Marfan Syndrome
Corpus Callosum
Cleft Lip
Skull Base
Cleft Palate
Autistic Disorder
Neuroimaging
Chromosomes
Growth

Keywords

  • 17p13.3
  • ABR
  • Autism
  • BHLHA9
  • Cleft lip/palate
  • LIS1
  • Marfanoid habitus
  • Microarray
  • Split hand foot long bone deficiency
  • YWHAE

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

The duplication 17p13.3 phenotype : Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes. / Curry, Cynthia J.; Rosenfeld, Jill A.; Grant, Erica; Gripp, Karen W.; Anderson, Carol; Aylsworth, Arthur S.; Saad, Taha Ben; Chizhikov, Victor V.; Dybose, Giedre; Fagerberg, Christina; Falco, Michelle; Fels, Christina; Fichera, Marco; Graakjaer, Jesper; Greco, Donatella; Hair, Jennifer; Hopkins, Elizabeth; Huggins, Marlene; Ladda, Roger; Li, Chumei; Moeschler, John; Nowaczyk, Malgorzata J M; Ozmore, Jillian R.; Reitano, Santina; Romano, Corrado; Roos, Laura; Schnur, Rhonda E.; Sell, Susan; Suwannarat, Pim; Svaneby, Dea; Szybowska, Marta; Tarnopolsky, Mark; Tervo, Raymond; Tsai, Anne; Tucker, Megan; Vallee, Stephanie; Wheeler, Ferrin C.; Zand, Dina J.; Barkovich, A. James; Aradhya, Swaroop; Shaffer, Lisa G.; Dobyns, William B.

In: American Journal of Medical Genetics, Part A, Vol. 161, No. 8, 08.2013, p. 1833-1852.

Research output: Contribution to journalArticle

Curry, CJ, Rosenfeld, JA, Grant, E, Gripp, KW, Anderson, C, Aylsworth, AS, Saad, TB, Chizhikov, VV, Dybose, G, Fagerberg, C, Falco, M, Fels, C, Fichera, M, Graakjaer, J, Greco, D, Hair, J, Hopkins, E, Huggins, M, Ladda, R, Li, C, Moeschler, J, Nowaczyk, MJM, Ozmore, JR, Reitano, S, Romano, C, Roos, L, Schnur, RE, Sell, S, Suwannarat, P, Svaneby, D, Szybowska, M, Tarnopolsky, M, Tervo, R, Tsai, A, Tucker, M, Vallee, S, Wheeler, FC, Zand, DJ, Barkovich, AJ, Aradhya, S, Shaffer, LG & Dobyns, WB 2013, 'The duplication 17p13.3 phenotype: Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes', American Journal of Medical Genetics, Part A, vol. 161, no. 8, pp. 1833-1852. https://doi.org/10.1002/ajmg.a.35996
Curry, Cynthia J. ; Rosenfeld, Jill A. ; Grant, Erica ; Gripp, Karen W. ; Anderson, Carol ; Aylsworth, Arthur S. ; Saad, Taha Ben ; Chizhikov, Victor V. ; Dybose, Giedre ; Fagerberg, Christina ; Falco, Michelle ; Fels, Christina ; Fichera, Marco ; Graakjaer, Jesper ; Greco, Donatella ; Hair, Jennifer ; Hopkins, Elizabeth ; Huggins, Marlene ; Ladda, Roger ; Li, Chumei ; Moeschler, John ; Nowaczyk, Malgorzata J M ; Ozmore, Jillian R. ; Reitano, Santina ; Romano, Corrado ; Roos, Laura ; Schnur, Rhonda E. ; Sell, Susan ; Suwannarat, Pim ; Svaneby, Dea ; Szybowska, Marta ; Tarnopolsky, Mark ; Tervo, Raymond ; Tsai, Anne ; Tucker, Megan ; Vallee, Stephanie ; Wheeler, Ferrin C. ; Zand, Dina J. ; Barkovich, A. James ; Aradhya, Swaroop ; Shaffer, Lisa G. ; Dobyns, William B. / The duplication 17p13.3 phenotype : Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes. In: American Journal of Medical Genetics, Part A. 2013 ; Vol. 161, No. 8. pp. 1833-1852.
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abstract = "Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.",
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T2 - Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes

AU - Curry, Cynthia J.

AU - Rosenfeld, Jill A.

AU - Grant, Erica

AU - Gripp, Karen W.

AU - Anderson, Carol

AU - Aylsworth, Arthur S.

AU - Saad, Taha Ben

AU - Chizhikov, Victor V.

AU - Dybose, Giedre

AU - Fagerberg, Christina

AU - Falco, Michelle

AU - Fels, Christina

AU - Fichera, Marco

AU - Graakjaer, Jesper

AU - Greco, Donatella

AU - Hair, Jennifer

AU - Hopkins, Elizabeth

AU - Huggins, Marlene

AU - Ladda, Roger

AU - Li, Chumei

AU - Moeschler, John

AU - Nowaczyk, Malgorzata J M

AU - Ozmore, Jillian R.

AU - Reitano, Santina

AU - Romano, Corrado

AU - Roos, Laura

AU - Schnur, Rhonda E.

AU - Sell, Susan

AU - Suwannarat, Pim

AU - Svaneby, Dea

AU - Szybowska, Marta

AU - Tarnopolsky, Mark

AU - Tervo, Raymond

AU - Tsai, Anne

AU - Tucker, Megan

AU - Vallee, Stephanie

AU - Wheeler, Ferrin C.

AU - Zand, Dina J.

AU - Barkovich, A. James

AU - Aradhya, Swaroop

AU - Shaffer, Lisa G.

AU - Dobyns, William B.

PY - 2013/8

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N2 - Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

AB - Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

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KW - BHLHA9

KW - Cleft lip/palate

KW - LIS1

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KW - Microarray

KW - Split hand foot long bone deficiency

KW - YWHAE

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