TY - JOUR

T1 - Phenotypes and genotypes in individuals with SMC1A variants

AU - Huisman, Sylvia

AU - Mulder, Paul A

AU - Redeker, Egbert

AU - Bader, Ingrid

AU - Bisgaard, Anne-Marie

AU - Brooks, Alice

AU - Cereda, Anna

AU - Cinca, Constanza

AU - Clark, Dinah

AU - Cormier-Daire, Valerie

AU - Deardorff, Matthew A

AU - Diderich, Karin

AU - Elting, Mariet

AU - van Essen, Anthonie

AU - FitzPatrick, David

AU - Gervasini, Cristina

AU - Gillessen-Kaesbach, Gabriele

AU - Girisha, Katta M

AU - Hilhorst-Hofstee, Yvonne

AU - Hopman, Saskia

AU - Horn, Denise

AU - Isrie, Mala

AU - Jansen, Sandra

AU - Jespersgaard, Cathrine

AU - Kaiser, Frank J

AU - Kaur, Maninder

AU - Kleefstra, Tjitske

AU - Krantz, Ian D

AU - Lakeman, Phillis

AU - Landlust, Annemiek

AU - Lessel, Davor

AU - Michot, Caroline

AU - Moss, Jo

AU - Noon, Sarah E

AU - Oliver, Chris

AU - Parenti, Ilaria

AU - Pie, Juan

AU - Ramos, Feliciano J

AU - Rieubland, Claudine

AU - Russo, Silvia

AU - Selicorni, Angelo

AU - Tümer, Zeynep

AU - Vorstenbosch, Rieneke

AU - Wenger, Tara L

AU - van Balkom, Ingrid

AU - Piening, Sigrid

AU - Wierzba, Jolanta

AU - Hennekam, Raoul C

N1 - © 2017 Wiley Periodicals, Inc.

PY - 2017/8

Y1 - 2017/8

N2 - SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

AB - SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

KW - Adolescent

KW - Adult

KW - Cell Cycle Proteins/genetics

KW - Child

KW - Child, Preschool

KW - Chromosomal Proteins, Non-Histone/genetics

KW - De Lange Syndrome/diagnosis

KW - Exome/genetics

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Middle Aged

KW - Netherlands/epidemiology

KW - Proteins/genetics

KW - Rett Syndrome/diagnosis

KW - Spasms, Infantile/diagnosis

KW - Young Adult

U2 - 10.1002/ajmg.a.38279

DO - 10.1002/ajmg.a.38279

M3 - Journal article

C2 - 28548707

VL - 173

SP - 2108

EP - 2125

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 8

ER -