Interstitial 6q21q23 duplication - variant of variable phenotype and incomplete penetrance or benign duplication?
BACKGROUND
Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known.


METHODS
We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members.


CONCLUSIONS
Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.
Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Malgorzata I
MI
Srebniak
Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Laura J C M
LJ
van Zutven
Department of Clinical Genetics, University Hospital, Lille, France.
Florence
F
Petit
Department of Cytogenetics, University Hospital, Lille, France.
Sonia
S
Bouquillon
Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Ilse P J
IP
van Heel
Department of Obstetrics and Gynecology, subdivision Obstetrics and Prenatal Medicine, Erasmus MC, Rotterdam, The Netherlands ; Stichting Prenatale Screening Zuidwest Nederland, Wytemaweg 80, Na-1509, 3015, GE Na-1503 Rotterdam, The Netherlands.
Maarten F C M
MF
Knapen
Department of Obstetrics and Gynecology, subdivision Obstetrics and Prenatal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Jerome M J
JM
Cornette
Department of Bioinformatics Erasmus MC, Rotterdam, The Netherlands.
Andreas
A
Kremer
Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Diane
D
Van Opstal
Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Karin E M
KE
Diderich
16p11.2 microduplication; Interstitial 6q22.1q23.2 duplication; Interstitial duplication 6q21q22.33; Second hit hypothesis; Susceptibility locus