A 5.3-Mb duplication of 9p12 --> p13.1 characterized by array CGH in a female infant with developmental delay.

The female infant was the first child of a 28-year-old mother and a 32-year-old father. The parents were healthy and non-consanguineous. The family history was unremarkable. The infant was delivered uneventfully at 38 weeks of gestation with a birth weight of 2,835 g. When examined at 8 months of age, the infant manifested developmental delay, a long face, low-set ears, hypopigmentation, trichiasis, entropion, astigmatism and mild edema of the lower part of the legs. Her body weight was 8.2 kg (50th centile), body length 68.2 cm (25-50th centile) and head circumference 43 cm (25-50th centile). When examined at 2 years and 4 months of age, she had speech delay, unstable gait, a body weight of 12 kg (25-50th centile), a body length of 89 cm (50th centile), a head circumference 46.8 cm (25-50th centile) and mild facial dysmorphism (Fig. 1). The cytogenetic analysis revealed a karyotype of 46,XX. Array CGH analysis identified a 5.3-Mb duplication of 9pl2^pl3.1 with the first abnormal clone located at 38,815,000 bp and the last abnormal clone at 44,135,000 bp (Fig. 2). The parents did not have such a duplication. Increase in length of the bands 9pl2 and 9pl3.1 could be observed on G-banding karyogram of the proband's lymphocytes (Fig. 3). The previously reported regions of extra G-band-positive, C-band-negative euchromatic variants include 8p23.1, 9pl2, 9ql2, 15ql 1.2-ql3, 16pll and 16pl 1.2 (1-5,8). The additional euchromatic bands are due to an amplified DNA cassette, and the additional material comprises pseudogenes (3, 7). Di Giacomo et al. (6) first reported duplication of 9pll.2-pl3.1 involving 5-5.2 Mb segment spanning from band 9pl 1.2 to the middle of band 9pl3.1 in two fetuses and their phenotypically normal mothers, and in one 33-year-old female with a normal phenotype and reproductive failure. Di Giacomo et al. (6) accordingly suggested that dup(9)(pll.2pl3.1) has no phenotypic or reproductive consequences in both sexes and is a benign cytogenetic variant. Lecce et al. (8) subsequently reported three additional cases of a similar polymorphism in a healthy 33-year-old woman and in two unrelated fetuses, both of whom had received the rearrangement from their healthy fathers, but found that it was a locus-specific amplification caused by repeated copies of a small DNA segment mapping within 9p 1 2 rather than a simple duplication. The present case was associated with de novo dup(9)(p 1 2p 1 3. 1 ) and phenotypic consequences. The duplication has spanned the whole band of 9pl3.l with gene dosage increase in the pseudogenes and the functional genes on 9pl3.l such as VN2R3P, CNTNAPi, FAM75A1, FAM75A2, FAM74AI, LOC647069 and LOC727745. VN2R1P is a vomeronasal 2 receptor 3 pseudogene. FAMI 5 Al and FAM75A2 are associated with hypothetical proteins LOC647060 and LOC642265, respectively. LOC647069 is similar to FKBP52 that encodes 52 kD FK506 binding protein which is a critical determinant of uterine progesterone actions in preparing the uterus for blastocyst implantation. LOC727745 is a hypothetical gene. CNTNAP3 (OMlM 6 1 05 1 7) encodes contactin-associated protein 3 which belongs to the neurexin family of multidomain transmembrane proteins that are involved in cell adhesion and intercellular communication, and are expressed in brain tissues and in other organs during fetal development and in the adult stage (9). As shown in this presentation, a duplication of 9pl3.l can be associated with phenotypic consequences. Although the extra G-band-positive material on 9pl2 has been well known to be a cuchromatic variant, we think that the genetic consequences of a chromosome duplication spanning from band 9pl2 to band 9pl3.1 should be interpreted with caution during genetic counseling, especially in the de novo cases. …