American Journal of Medical Genetics 137A:47–51 (2005) 22q11.2 Duplication Syndrome: Two New Familial Cases With Some Overlapping Features With DiGeorge/Velocardiofacial Syndromes Marie-France Portnoı ¨, 1 * Fanny Lebas, 2 Nicolas Gruchy, 1 Azarnouche Ardalan, 1 Vale ´ rie Biran-Mucignat, 2 Vale ´ rie Malan, 1 Lina Finkel, 1 Gilles Roger, 3 Sarah Ducrocq, 2 Francis Gold, 2 Jean-Louis Taillemite, 1 and Sandrine Marlin 4 1 Laboratoire de Cytoge´ne´tique, Hopital Saint-Antoine AP-HP, Paris, France 2 Service de Ne´onatologie, Hopital Armand-Tousseau AP-HP, Paris, France 3 Service d’Oto-Rhino-Laryngologie, Hopital Armand-Tousseau AP-HP, Paris, France 4 Unite´de Ge´ne´tique me´dicale, Hopital Armand-Tousseau AP-HP, Paris, France Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplica- tion 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7½-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodac- tyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hyper- telorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identifica- tion probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a com- bination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders. ß 2005 Wiley-Liss, Inc. KEY WORDS: 22q11.2 duplication; interphase FISH; chromosome 22; genomic disorder INTRODUCTION The chromosome 22q11.2 has long been implicated in genomic diseases such as DiGeorge /velocardiofacial syndrome (DG/VCFS), der(22) and cat-eye syndrome (CES), which are associated with either decreased or increased gene dosage [Edelmann et al., 1999b; Shaikh et al., 2000]. CES and der(22) syndrome are rare disorders characterized by duplications (tetrasomy and trisomy, respectively) of part of 22q11.2 [McDermid and Morrow, 2002]. The microdeletions of 22q11.2 that are associated with DG/VCFS occur more often in the general population, with an estimated frequency of 1/4,000 live births [Lindsay, 2001; Yamagishi, 2002; Botto et al., 2003]. These different congenital anomaly disorders share a physical region of overlap containing copies of chromosome 22-specific low-copy repeats (LCRs) [McDermid and Morrow, 2002]. LCR22s are presumed to predispose to homologous recombination events and to mediate nonallelic homologous recombinations that result in rearrangements of 22q11.2. Meiotic inter- or intra-chromosomal nonallelic homologous recombination events, due to unequal crossovers between LCR22s, might generate the common 3 Mb deletion in DG/ VCFS and the reciprocal 3 Mb interstitial duplication [Edelmann et al., 1999a,b; Shaikh et al., 2000, 2001]. Twenty-one patients with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or some overlapping features with DG/VCFS, have been shown to harbor a chromosome duplication 22q11 of the genomic region that is deleted in patients with DG/VCFS. The microduplication of 22q11.2, establishing the comple- mentary genomic disorder of the 22q11.2 deletion syndrome, appears to represent a new syndrome [Ensenauer et al., 2003; Hassed et al., 2004a]. All cases have been identified primarily by interphase FISH and could escape identification and are missed by routine cytogenetic analysis and probably have been underdiagnosed. We describe here two new familial cases with a duplication of 22q11.2, with some overlapping features with DG/VCF syndrome, determined by FISH studies. CLINICAL REPORTS Patient 1 The patient was born at term to a 23-year-old G2P1 mother and to a 39-year-old father. Her birthweight was 2,920 g, *Correspondence to: Marie-France Portnoı ¨, Laboratoire de Cytoge ´ne ´tique, Ho ˆpital Saint-Antoine 75012 Paris, France. E-mail: marie-france.portnoi@sat.ap-hop-paris.fr Received 9 December 2004; Accepted 30 May 2005 DOI 10.1002/ajmg.a.30847 ß 2005 Wiley-Liss, Inc.