Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities.
Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.
Ballif
Blake C
BC
Signature Genomic Laboratories, Spokane, WA 99207, USA. ballif@signaturegenomics.com
Theisen
Aaron
A
Rosenfeld
Jill A
JA
Traylor
Ryan N
RN
Gastier-Foster
Julie
J
Thrush
Devon Lamb
DL
Astbury
Caroline
C
Bartholomew
Dennis
D
McBride
Kim L
KL
Pyatt
Robert E
RE
Shane
Kate
K
Smith
Wendy E
WE
Banks
Valerie
V
Gallentine
William B
WB
Brock
Pamela
P
Rudd
M Katharine
MK
Adam
Margaret P
MP
Keene
Julia A
JA
Phillips
John A
JA
Pfotenhauer
Jean P
JP
Gowans
Gordon C
GC
Stankiewicz
Pawel
P
Bejjani
Bassem A
BA
Shaffer
Lisa G
LG
D000293:Adolescent; D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D019465:Craniofacial Abnormalities / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011995:Recombination, Genetic; D056916:Segmental Duplications, Genomic; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000235:genetics
C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; C491193:TBX4 protein, human