When is karyotyping recommended?

When is Karyotyping Recommended?

Karyotyping should be performed as a first-line test when common aneuploidies (trisomy 21,18, or sex chromosome abnormalities) are suspected, when evaluating balanced chromosomal rearrangements, in cases of family history of chromosomal rearrangements in phenotypically normal individuals, and in couples with multiple miscarriages. 1, 2

Postnatal Indications for Karyotyping

Developmental and Congenital Abnormalities

• Karyotyping is appropriate when common aneuploidy is suspected clinically (e.g., Down syndrome phenotype), as conventional cytogenetics can provide results within 48 hours and is more cost-effective than microarray for well-recognized syndromes. 1
• Blood chromosome analysis should be performed on newborns with dysmorphic features or suspected chromosomal abnormalities, with a minimum 550-band resolution, even when prenatal testing was normal, as mosaicism may have been undetected. 3
• However, chromosomal microarray analysis (CMA) is recommended as the first-line test for multiple anomalies not specific to a well-delineated syndrome, apparently nonsyndromic developmental delay/intellectual disability, and autism spectrum disorders, as it has a higher diagnostic yield (10%) compared to karyotyping (3.7%). 1, 2

Malformations of Cortical Development

• Karyotype analysis should be considered in undiagnosed patients with malformations of cortical development (MCDs), particularly when microcephaly is present, as chromosomal aneuploidies and copy number variants account for genetic causes in approximately 30% of microcephaly cases. 1
• This testing is especially important when there is recurrence in the family, dysmorphic features, or congenital abnormalities outside the central nervous system. 1

Male Infertility Indications

Severe Oligozoospermia and Azoospermia

• Karyotype testing should be performed on all males with severe oligozoospermia (<5 × 10⁶/ml) or non-obstructive azoospermia prior to any therapeutic procedure (ICSI using ejaculated sperm or testicular sperm extraction). 1
• Men with sperm counts <5 million/ml show approximately 4% rate of autosomal abnormalities, with the highest frequency in non-obstructive azoospermia (mostly Klinefelter syndrome). 1
• The a priori knowledge of chromosomal translocations allows for preimplantation genetic screening to transfer only balanced or normal embryos while discarding chromosomally unbalanced ones. 1

Recurrent Pregnancy Loss

Risk-Stratified Approach

• Karyotyping should be offered to couples with recurrent pregnancy loss after individual risk assessment, particularly when there is a previous live birth with congenital anomalies or detection of unbalanced chromosomes/translocation in products of conception or chorionic villi/amniotic fluid samples. 4
• Balanced chromosomal rearrangements (reciprocal and Robertsonian translocations) are found in approximately 1.9-3.8% of couples with recurrent miscarriage, with chromosomes 8,11,14, and 21 most frequently involved. 4, 5
• In the absence of positive history, routine karyotyping of all couples may not be cost-effective, as only 10% of karyotyped abortuses show the parental aberration passed on, and 43.5% of abortuses are euploidic even when parents carry chromosomal aberrations. 4, 6

Hematologic Malignancies

Acute Myeloid Leukemia

• Conventional cytogenetics should be performed at diagnosis of acute myeloid leukemia, with results obtained preferably within 5-7 days, requiring at least 20 bone marrow metaphases to define a normal karyotype. 1
• Karyotype analysis identifies powerful prognostic factors including complex karyotype associated with TP53 mutations, which guide treatment decisions and risk stratification. 1

Critical Limitations of Karyotyping

When NOT to Use Karyotyping

• Do not order karyotyping when rapid turnaround time is needed (e.g., STAT newborn analysis), as it requires 48 hours minimum, whereas some clinical decisions require faster results. 1
• Karyotyping cannot detect balanced chromosomal rearrangements when using array-based methods, cannot identify low-level mosaicism reliably, and may miss marker chromosomes depending on size and composition. 1
• For suspected microdeletion syndromes (e.g., Williams syndrome), FISH with a single probe is more cost-effective than karyotyping. 1

When to Follow Up with Additional Testing

• If peripheral blood karyotype is normal but clinical suspicion remains high, skin fibroblast culture can detect mosaicism not present in circulating T-lymphocytes, as certain chromosomal abnormalities are only detectable in fibroblasts. 3
• Extended chromosome analysis with additional cell counts or interphase FISH should follow initial blood karyotype if the phenotype suggests mosaicism. 3