The patient, BSB, was a 6-year-old girl, the product of the third pregnancy of a healthy, nonconsanguineous young couple with a previous history of two miscarriages. The pregnancy was uneventful. The mother reported that her younger sister also had three miscarriages, and her older sister gave birth to four normal children.
The patient was born by vaginal delivery at 36 weeks of gestation, presenting polyhydramnios, a birth weight of 2750 g (50th percentile) and birth length of 46 cm (50th percentile); her head circumference was 32 cm (50th percentile), and the Apgar scores were 6 and 8. She was kept in intensive care for 3 days due to respiratory distress. At the age of 2 months, she had difficulties in responding to sound stimuli, as a consequence of bilateral otitis. At 6 months, she underwent surgery for the correction of bilateral inguinal and umbilical hernia. Clinical evaluation at the age of six years showed failure to thrive, along with intellectual disability, hearing impairment, speech delay and dysphagia. Physical examination showed a high-set hairline, mild synophrys, ocular hypertelorism, upslanting palpebral fissures, a flat-bridged and broad-based nose, hypoplastic nostrils, prominent columella, long filtrum, thin upper lip, prominent chin and wide mouth with conical teeth. Her hands showed few palmar creases, clinodactyly of the 5th fingers, persistence of digital pads, and her toes had prominent interdigital folds. Some of these features can be seen in Figure 1.
X-rays of hands and feet showed no abnormalities, and a cranial CT scan and MRI were normal. The patient's early development was severely delayed, with a pronounced deficit in the acquisition of motor, language and social skills. Due to a sucking and swallowing disability, she showed difficulties in gaining weight. She displayed good behavior and a docile personality.
Upon initial analysis, the proposita's karyotype was determined as being 47,XX,+mar. C-banding and NOR-staining characterized the marker as a monocentric and monosatellited chromosome. A cytogenetic evaluation of the family revealed a 46,XX,t(15;16)(q13;p13.2) karyotype in the mother and one aunt, and a 46,XY,t(15;16)(q13;p13.2) karyotype in the maternal grandfather. The patient's karyotype was therefore redefined as 47,XX,+der(15)t(15;16)(q13;p13.2)mat.
Array-CGH analysis revealed a duplication of about 3.1 Mb of the proximal 15q segment (chr15:18,741,516-21,856,312), comprising TUBGCP5, CYFIP1, NIPA2 genes, and unexpectedly also showed a 1.3 Mb duplication of a distal 16p segment (chr16:2,056,890-3,346,212), comprising TBC1D24; PKD1; THOC6 genes, as well as a small duplication (0.6 Mb) of a proximal 16p segment (chr16:32,748,149-33,316,84). FISH analysis using a centromeric 15 probe and a WCP16 probe confirmed the involvement of chromosomes 15 and 16 in the rearrangement (Figure 2). The breakpoint and intervals of the duplications were entered into the UCSC Genome Browser to search for gene content and function, and were confirmed by the NCBI Map Viewer (http://www.ncbi.nlm.nih.gov/projects/mapview/). DECIPHER (https://decipher.sanger.ac.uk/) and DGV - Database of Genomic Variants: http://dgv.tcag.ca/dgv/app/home were also used to analyze the imbalanced regions.