title: A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review.
abstract: BACKGROUND
  Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date.
  
  
  METHODS
  We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents.
  
  
  RESULTS
  Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping.
  
  
  CONCLUSIONS
  The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain. lfernandez.hulp@salud.madrid.org
authors.forename: Luis
authors.initials: L
authors.lastname: Fernández
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.forename: Damià
authors.initials: D
authors.lastname: Heine-Suñer
authors.forename: Victor
authors.initials: V
authors.lastname: Martinez-Glez
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaur
authors.forename: Rebeca
authors.initials: R
authors.lastname: Palomo
authors.forename: Alicia
authors.initials: A
authors.lastname: Delicado
authors.forename: Isidora López
authors.initials: IL
authors.lastname: Pajares
authors.forename: María
authors.initials: M
authors.lastname: Palomares
authors.forename: Luis
authors.initials: L
authors.lastname: García-Guereta
authors.forename: Eva
authors.initials: E
authors.lastname: Valverde
authors.forename: Federico
authors.initials: F
authors.lastname: Hawkins
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
mesh_terms: D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D018628:Gene Dosage; D020440:Gene Duplication; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000601:surgery; D006345:Heart Septal Defects, Ventricular / Q000235:genetics* / Q000601:surgery; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007621:Karyotyping; D008297:Male; D021141:Nucleic Acid Amplification Techniques; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome