These studies were approved by appropriate ethics boards in Canada and the UK.
Vancouver patient 5566
Patient 5566, a girl, was the second child born after an uncomplicated 38 week gestation to healthy non‐related parents of English–Canadian descent. Their first child is a healthy boy. The family history is unremarkable except for cutaneous syndactyly of both second and third toes in the maternal grandfather and maternal great‐aunts.
The infant's birth weight was 3900 g (91st percentile), birth length, 54 cm (98th percentile) and birth head circumference, 38 cm (99.6th percentile). She had prominent strawberry naevi over her left eyelid, philtrum and occiput at birth. The occipital naevus has persisted, whereas the others have faded. She had hypotonia as an infant that resolved as she grew older.
On evaluation at 28 months of age, her height was 89 cm (75th percentile), weight 12 kg (25th percentile) and head circumference 51.5 cm (97th percentile). She had mildly dysmorphic facies (figure 1A) with short palpebral fissures (5th percentile). Her eyebrows were rounded with a triangular medial aspect and distal tapering. She had normally positioned ears with unusual auricles in which the helical root swept into a horizontal bar of cartilage dividing the concha into a lower and an upper portion, limited superiorly by a horizontal inferior crux of the antihelix (figure 1A). The posterior portion of the helix and antihelix were fused bilaterally. She had a short nose with small nasal tip and flat nasal bridge, long philtrum and small mouth with prominent Cupid's bow of the upper lip. She also had micrognathia. Her heels were prominent and her feet were flat with cutaneous syndactyly of the second and third toes. Formal developmental assessment at 4.5 years of age found her gross motor skills in the 2–3‐year range and fine motor skills in the 3–4‐year range.
Cytogenetic analysis at >550 band resolution showed a normal female karyotype. AGH (GeneChip Mapping 100K Assay; Affymetrix, Santa Clara, California, USA) on patient 5566 and both her parents showed a de novo deletion of around 200 kb of chromosome 14q11.2.4
The presence and de novo status of the CNV were confirmed by fluorescence in situ hybridisation (FISH).4
Owing to the small size of the lesion, we reanalysed the child and both parents by AGH using the Affymetrix 500K assay and found the deletion to be only 101 kb, with breakpoints at 20
740 bp and 20
178 bp based on the locations of the most proximal and distal deleted SNPs respectively (UCSC build hg18, March 2006) (figure 2). The chromosome with the deletion is probably maternal, based on presence of one informative paternal single nucleotide polymorphism (SNP) in the interval.
Figure 2SNP genotyping data on patient 5566 and both her parents by AGH using Affymetrix 500K (top panel) and 100K (bottom panel) Genechip assays. (A) Child vs father comparison; (B) child vs mother comparison; (C) child vs father comparison; (more ...)
Vancouver patient 8326
Patient 8326, a boy, was the first child of healthy unrelated parents of Japanese descent. He was born at 37 weeks' gestation after an uncomplicated pregnancy and normal vaginal delivery. The family history is non‐contributory.
At birth, weight was 2730 g (~50th percentile), length 51 cm (75th percentile) and head circumference 32 cm (10th percentile). The neonatal course was complicated by respiratory distress, and a ventricular septal defect and large patent ductus arteriosus were diagnosed by echocardiogram. The ductus was ligated at 10 days of age and the septal defect closed spontaneously by 6 months. There were no subsequent cardiac problems.
The patient has a history of hypotonia, acquiring good head control only at 6 months. Walking was achieved at 2 years. He also showed delays in fine motor and language skills. A Gesell developmental test at 26 months of age estimated his gross and fine motor skills at the 13‐month level, adaptive skills at the 11–13‐month level and language skills at the 15‐month level. Ophthalmological and auditory evaluations were both normal. On physical examination at 44 months, his height was 97.7 cm (25th percentile), weight 13.8 kg (10th percentile) and head circumference, 49 cm (25th percentile). He had mildly dysmorphic facies (figure 1B) with a broad forehead, epicanthic folds, very short palpebral fissures (2 SD below the mean) and rounded eyebrows with a triangular medial aspect and distal tapering. The nose was small with a very flat broad nasal bridge and small nasal tip. The ears were normally placed with malformed auricles that were remarkably similar to those of patient 5566 (figure 1b). He also had a small mouth, a very narrow high‐arched palate, a long philtrum and a prominent Cupid's bow. He had a bridged palmar crease on the right hand and a single palmar crease on the left hand. He had significant pronation of the left foot, mild syndactyly of the second and third toes and clinodactyly of both fourth toes.
Cytogenetic analysis at >550‐band resolution showed a normal male karyotype. AGH on the child and both his parents (GeneChip Mapping 100K Assay; Affymetrix) showed a de novo deletion of ~1.6 Mb at chromosome 14q11.2, with proximal and distal breakpoints at 19
863 bp and 21
935 bp (UCSC build hg18, March 2006), respectively.4
The presence and de novo status of this deletion were confirmed by FISH.4
SNP genotype data determined the deletion‐bearing chromosome to be paternal.
DECIPHER patient 126
DECIPHER paitent 126, a girl, was the first child of healthy unrelated parents of English descent with no relevant family history. She was born at 40 weeks' gestation by emergency caesarean section for fetal distress, weighing 3657 g (50–75th percentile). She did not require resuscitation but was admitted to the neonatal unit with respiratory problems and required nasogastric feeding for the first few days of life. At 6–8 weeks of age, she still had marked head lag and was generally hypotonic. Her first year of life was characterised by lack of social interaction. She had a brief febrile convulsion at 10 months and sat at 11 months of age.
On review at 14 months, she did not make eye contact and demonstrated hand regard and bruxism. She walked at 26 months. At 29 months, her developmental level was assessed at the 12–17‐month range, with speech and language skills and spontaneous play both at approximately the 10‐month level. A moderate left alternate convergent squint and hypermetropia were noted. She had rather deep‐set eyes, a prominent philtrum and prominent antihelix of both ears (figure 1C).
On review at 58 months, she had some single words, and showed an increased desire to communicate and some imitative play. On physical examination, height was 102 cm (9th percentile), weight 15.9 kg (9th–25th percentile) and head circumference 50.7 cm (9th–25th percentile).
Cytogenetic analysis at >550‐band resolution and cranial MRI scan were normal. A multiplex ligation dependent probe amplification‐based telomere assay showed deletion of one of the ‘control' regions on chromosome 14q11. FISH analysis demonstrated a de novo deletion of the region defined by clones RP11‐203M5 and RP11‐524O1 on chromosome 14q11.2, identifying a ~1.079 Mb minimal deletion from 19
310 to 20
827 bp (UCSC build hg18, March 2006). The deletion is flanked by the clones RP11‐597A11 (19.2 Mb) and RP11‐124D2 (22.8 Mb), both of which are present in two copies. Studies of her parents confirmed that the deletion was de novo.
The parental origin of the deletion‐bearing chromosome was not determined.