Two maternal duplications involving the CDKN1C gene are associated with contrasting growth phenotypes.
BACKGROUND
The overgrowth-associated Beckwith-Wiedemann syndrome (BWS) and the undergrowth-associated Silver-Russell syndrome (SRS) are characterized by heterogeneous molecular defects affecting a large imprinted gene cluster at chromosome 11p15.5-p15.4. While maternal and paternal duplications of the entire cluster consistently result in SRS and BWS, respectively, the phenotypes associated with smaller duplications are difficult to predict due to the complexity of imprinting regulation. Here, we describe two cases with novel inherited partial duplications of the centromeric domain on chromosome 11p15 associated with contrasting growth phenotypes.


RESULTS
In a male patient affected by intrauterine growth restriction and postnatal short stature, we identified an in cis maternally inherited duplication of 0.88 Mb including the CDKN1C gene that was significantly up-regulated. The duplication did not include the long non-coding RNA KCNQ1OT1 nor the imprinting control region of the centromeric domain (KCNQ1OT1:TSS-DMR or ICR2) in which methylation was normal. In the mother, also referring a growth restriction phenotype in her infancy, the duplication was de novo and present on her paternal chromosome. A different in cis maternal duplication, 1.13 Mb long and including the abovementioned duplication, was observed in a child affected by Tetralogy of Fallot but with normal growth. In this case, the rearrangement also included most of the KCNQ1OT1 gene and resulted in ICR2 loss of methylation (LOM). In this second family, the mother carried the duplication on her paternal chromosome and showed a normal growth phenotype as well.


CONCLUSIONS
We report two novel in cis microduplications encompassing part of the centromeric domain of the 11p15.5-p15.4 imprinted gene cluster and both including the growth inhibitor CDKN1C gene. Likely, as a consequence of the differential involvement of the regulatory KCNQ1OT1 RNA and ICR2, the smaller duplication is associated with growth restriction on both maternal and paternal transmissions, while the larger duplication, although it includes the smaller one, does not result in any growth anomaly. Our study provides further insights into the phenotypes associated with imprinted gene alterations and highlights the importance of carefully evaluating the affected genes and regulatory elements for accurate genetic counselling of the 11p15 chromosomal rearrangements.
Department of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Susanne Eriksen
SE
Boonen
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy.
Andrea
A
Freschi
Department of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Rikke
R
Christensen
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy.
Federica Maria
FM
Valente
Department of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Dorte Launholt
DL
Lildballe
Dipartimento di Biologia, Tigem, Napoli, Italy.
Lucia
L
Perone
Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG Italy.
Orazio
O
Palumbo
Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG Italy.
Massimo
M
Carella
Department of Obstetrics and Gynecology, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Niels
N
Uldbjerg
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy.
Angela
A
Sparago
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy.|Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso", Consiglio Nazionale delle Ricerche CNR, Napoli, Italy.
Andrea
A
Riccio
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Caserta, Italy.
Flavia
0000-0003-3794-3021
F
Cerrato
D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D020440:Gene Duplication; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57
CDKN1C; Genomic imprinting; Growth disorders; KCNQ1OT1; Microduplications