BackgroundThe 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level. To our knowledge, the 8p23.1 duplication syndrome has been described at prenatal diagnosis only once and we report our experience with four further apparent duplications ascertained at prenatal diagnosis.MethodsAdditional material at band 8p23.1 was detected using conventional G-banded cytogenetics in each case. Multiplex Ligation-dependent Probe Amplification (MLPA) or Fluorescence In Situ Hybridisation (FISH) were used depending on whether only DNA (Cases 1 and 4) or cytogenetic preparations (Cases 2 and 3) were available from the laboratory of origin. The extent of the duplication in Case 1 was retrospectively determined using array Comparative Genomic Hybridisation (array CGH).ResultsThree cases of 8p23.1 duplication syndrome were found (Cases 1 to 3). Two were de novo and continued to term and the third, a paternally transmitted duplication, was terminated because of a previous child with psychomotor delay and 8p23.1 duplication syndrome. Case 1 was ascertained with a hypoplastic left heart but the ventricular septal and interventricular defects, in Cases 2 and 3 respectively, were found after ascertainment for advanced maternal age. By contrast, case 4 was a maternally transmitted copy number variation of the defensin cluster with normal outcome.ConclusionsOur data underline the need to differentiate 8p23.1 duplications from copy number variation of the defensin cluster using FISH, MLPA or array CGH. Cardiac defects were ascertained by ultrasound in only one of the three duplication 8p23.1 pregnancies but were visible in two of the three at 21 to 22 weeks gestation. Our results provide further evidence that both deletion and duplication of the GATA4 transcription factor can give rise to a variety of conotruncal heart defects with variable penetrance and expressivity.
Deletions of. the distal region of the long arm of chromosome 4 are well documented and characterised, whereas deletions ofthe proximal region are apparently rare. We report another child with a proximal interstitial deletion of chromosome 4, del(4)(q12q21.1), and multiple congenital anomalies, including bilateral colobomata, which has not previously been described in patients with similar deletions.The proband was the second child of a 22 year old mother and 47 year old father who were healthy and unrelated. He has three sibs and five half sibs, all phenotypically normal. Delivery was at 41 weeks after an unremarkable pregnancy. There was fetal distress during the second stage, but a spontaneous vaginal delivery occurred before obstetric intervention could be arranged. Apgar scores were 9 and 10 at one and five minutes respectively. Birth weight was 3240 g (10th centile), length 52 cm (50th centile), and head circumference 35-5 cm (50th centile).The baby was referred for cytogenetic investigation on day 14 because of abnormal facial appearance, poor feeding, and an apnoeic episode. He was noted to be hypotonic and to have bilateral iris colobomata. Further ophthalmic examination showed right microphthalnia with a coloboma involving the optic disc and macula. The coloboma on the left involved part of the optic disc with sparing of the macula. Additional dysmorphic features were a high arched palate and widely spaced nipples. He had a transient heart murmur. Skull and spinal x rays, CT scan, and ultrasound examination of the head showed no further abnormalities.His growth and development have been delayed and on re-examination at 3 years 10 months his head circumference and weight had fallen below the 3rd centile. His head was an unusual shape with bitemporal narrowing and sparse hair (fig 1). He sat with support but had developed a scoliosis. He had a persistent nasal discharge although there was no evidence of choanal atresia. He had bilateral deafness but responded to loud low notes.Cytogenetic analysis of a peripheral blood sample using GTG and RBG banding indicated an interstitial deletion of the proximal region of the long arm of chromosome 4 (fig 2). The karyotype was interpreted as 46,XY,del(4)(pter-qql2::q21.1--qter). Parental karyotypes were normal.
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