title: Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism.
abstract: The 17q21.31 microdeletion syndrome is characterised by intellectual disability, epilepsy, distinctive facial dysmorphism, and congenital anomalies. To date, all individuals reported with this syndrome have been simplex patients, resulting from de novo deletions. Here, we report sibling recurrence of the 17q21.31 microdeletion syndrome in two independent families. In both families, the mother was confirmed to be the parent-of-origin for the 17q21.31 deletion. Fluorescence in situ hybridisation analyses in buccal mucosa cells, of the mother of family 1, identified monosomy 17q21.31 in 4/50 nuclei (8%). In mother of family 2, the deletion was identified in 2/60 (3%) metaphase and in 3/100 (3%) interphase nuclei in peripheral lymphocytes, and in 7/100 (7%) interphase nuclei in buccal cells. A common 17q21.31 inversion polymorphism predisposes to non-allelic homologous recombination and hereby to the 17q21.31 microdeletion syndrome. On the basis of the 17q21.31 inversion status of the parents, we calculated that the probability of the second deletion occurring by chance alone was 1/14,438 and 1/4812, respectively. If the inversion status of the parents of a child with the 17q21.31 microdeletion syndrome is unknown, the overall risk of a second child with the 17q21.31 microdeletion is 1/9461. We conclude that the presence of low-level maternal somatic-gonadal mosaicism is associated with the microdeletion recurrence in these families. This suggests that the recurrence risk for parents with a child with a 17q21.31 microdeletion for future pregnancies is higher than by chance alone and testing for mosaicism in the parents might be considered as a helpful tool in the genetic counselling.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. d.koolen@antrg.umcn.nl
authors.forename: David A
authors.initials: DA
authors.lastname: Koolen
authors.forename: Juliette
authors.initials: J
authors.lastname: Dupont
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Simone P A
authors.initials: SP
authors.lastname: van den Heuvel
authors.forename: Alyson
authors.initials: A
authors.lastname: Bradbury
authors.forename: James
authors.initials: J
authors.lastname: Steer
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Leo P
authors.initials: LP
authors.lastname: Ten Kate
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
mesh_terms: D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006239:Haplotypes; D059765:Homologous Recombination; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D007399:Interphase; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008677:Metaphase; D009030:Mosaicism; D010375:Pedigree; D012307:Risk Factors; D013577:Syndrome