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Case 1: Ms. Sanfilippo is a 25-year-old gravida 5 para 3104 whose first-trimester screen gave her a 1:1200 risk of Down syndrome and <1:5000 risk of trisomy 18, and a second-trimester alpha fetoprotein was in the normal range (1.2 MOM). She has no significant past medical history. Her obstetric history was significant for a previous term spontaneous vaginal delivery complicated by a rectovaginal fistula. This was followed by a term cesarean delivery, and her last pregnancy was a preterm repeat cesarean at 34 weeks. A three generation family history was significant for Hirschsprung disease in a son with a previous partner. An initial anatomy ultrasound at 18 weeks of gestation was performed at an outside hospital, and showed the fetus to have a left sided diaphragmatic hernia with cardiac displacement to the right side of the chest. The patient was referred to a regional center because of the abnormal ultrasound. A repeat ultrasound at 20 weeks of gestation identified a thickened nuchal fold of 7 mm, bilateral echogenic kidneys with nephromegaly, and a left-sided diaphragmatic hernia. Ms. Sanfilippo was counseled about the risks and benefits of amniocentesis. Rapid FISH analysis was performed on 50 interphase cells from the amniotic fluid with #13, #18, #21, X-, and Y-specific probes. No evidence of trisomy 13, 18, or 21 was detected. Analysis of the X and Y probe revealed two copies of the X probe and no copies of the Y probe, consistent with 46,XX female karyotype. FISH analysis was also performed using probes specific for chromosome 12 to rule out mosaic isochromosome 12p (Pallister-Killian syndrome), and the results were consistent with normal chromosome 12. Fifteen cells were analyzed from the amniotic fluid specimen. No significant numerical or structural aberrations were seen at the 475 G-band level of resolution. The karyotype was reported as normal, 46,XX female. Since the karyotype and FISH results were both normal, an oligonucleotide microarray was performed. Microarray-based comparative genomic hybridization (aCGH), also known as chromosomal microarray technique (CMA) was performed using a 135K-feature whole-genome microarray. Microarray revealed a 1.4-Mb deletion on 17q12. Neither parent carried the deletion; therefore this deletion was a de novo finding. The deletion caused haploinsufficiency for 17 genes, including AATF, ACACA, DDX52, DUSP14, GGNBP2, HNF1B, LHX1, PIGW, SYNRG, TADA2A, and ZNHIT3. The deleted region on 17q12 is similar in size and gene content to the previously reported 17q12 microdeletion syndrome.1 The 17q12 microdeletion syndrome has been associated with MODY5 (maturity-onset of diabetes of the young, type 5), cystic renal disease, pancreatic atrophy, liver abnormalities, cognitive impairment, and structural brain abnormalities. Ms. Sanfilippo was counseled with regards to the diagnosis and prognosis. The risk of recurrence is at most 2% to 3%, as gonadal mosaicism cannot be ruled out. After reviewing the risks and prognosis associated with congenital diaphragmatic hernia and 17q12 microdeletion syndrome, Ms. Sanfilippo opted for comfort measures after her baby is born.

Chromosomal abnormalities occur in germ cell division (meiosis), during early fetal development, or after birth in any cell in the body (mitosis) (see Chapter 2). The number, structure, properties of chromosomes, chromosomal behavior, and influence of chromosomal abnormalities on the phenotype are studied in cytogenetics. The analysis of chromosomes in human development and disease is accomplished through classical cytogenetic procedures, including Giemsa or G-banding karyotype analysis and C-(constitutive heterochromatin) banding. Molecular techniques such as array comparative genomic hybridization (aCGH/CMA) and single nucleotide polymorphism microarray (SNP microarray) analyses have improved resolution, and have replaced the karyotype in many clinical situations as the first line technique to detect genomic imbalances.


Cells duplicate their genetic material and generate genetically identical daughter cells during mitosis. Chromosome morphology can be visualized and studied under the light microscope during the prophase or metaphase of the mitotic cell division, when chromosomes are condensed. During metaphase, replicated chromosomes are aligned and sister chromatids are ready for separation to the opposite poles along the spindle fibers. Colchicine, a spindle inhibitor, added to the cell culture, disrupts the spindle-fiber complex and arrests mitosis. The chromosomes, when stained with a dye (Giemsa), have a distinct banded pattern (G-banding) that provides a unique bar code to each chromosome (Figure 15-1). Chromosomes become gradually shortened as the cell cycle progresses from interphase to metaphase. Depending on the degree of chromosome condensation, the chromosomes reveal from 400 to 850 bands per haploid genome, which enables detection of chromosomal alterations with resolution to the 5 to 10 Mb level by routine microscopic analysis. High-resolution chromosome studies (600-850 bands) allow a more detailed analysis of the chromosome structure, as compared to the 400 to 550 bands observed with routine metaphase banding. The karyotype provides an overview of the whole genome and detects both numerical and gross structural chromosomal aberrations.

Figure 15-1.

A human normal male karyotype. Homologous chromosomes (homologues), the two chromosomes in a pair of autosomes, are composed of similar ...

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