Writing guidance for letters of medical necessity for
Chromosomal Microarray testing (CMA)
Materials & References
Developmental Delay

In order to test [Patient Name] for the most common known genetic causes of developmental delays, we
recommend chromosomal microarray analysis (CMA). CMA analyzes the genome for gains or losses of genetic
material at a much higher resolution than standard karyotype analysis. CMA has the ability to detect small gains or
losses in genetic material that may have been missed on standard blood chromosome analysis alone. A 2006 policy
statement from the American Academy of Pediatrics stated that cytogenetic studies were “to be expected” in a child
with developmental delay of unknown etiology (Pediatrics 2006 117: 2304-2316). At the time those guidelines were
written, CMA was considered an emerging technology, but subsequent publications have documented the improved
diagnostic yield of CMA and support the use of CMA as a first-tier test. A review of over 36,000 patients presenting
with developmental delays/intellectual disabilities found that CMA identified a pathogenic abnormality in
approximately 19% of cases (Hochstenbach et al. (2009) Eur J Hum Genet 52:161-169). Further, an investigation of
the diagnostic yield of various genetic tests used in the evaluation of patients with developmental delays revealed
that CMA had the highest yield of any single test at approximately 29% (Rauch et al. 2006 Am J Med Genet
140:2063-2074). Citing large-scale studies such as these, the American College of Medical Genetics has recently
officially endorsed CMA as a “first line test” in the evaluation of individuals with unexplained developmental delays
(Manning and Hudgins (2010) Genet in Med 12(11): 742-745).

Chromosomal microarray analysis (CMA) has been found to have the highest yield of any single diagnostic test in
individuals with developmental delays, intellectual disabilities, and cognitive impairment. Large scale studies on tens
of thousands of patients (Hochstenbach et al. (2009) Eur J Hum Genet. 52:161-169; Rauch et al. (2006) Am J Med
Genet. 140: 2063-2074) have demonstrated anywhere from a 19% to a 29% detection rate for a clinically significant,
submicroscopic chromosomal abnormality. Based on these and many other studies, the American College of
Medical Genetics published a practice guideline in which CMA was recommended as a “first line test” in the
evaluation of individuals with unexplained developmental delays, and is now considered standard-of-care (Manning
and Hudgins (2010) Genet in Med 12(11): 742-745).
Autism

In order to test [Patient Name] for the most common known genetic causes of autism, we recommend
chromosomal microarray analysis (CMA). CMA analyzes the genome for gains or losses of genetic material at a
much higher resolution than standard karyotype analysis. CMA has the ability to detect small gains or losses in
genetic material that may have been missed on standard blood chromosome analysis alone. In general, amongst
individuals with autism such as [Patient Name], CMA is able to identify a cytogenetic cause in approximately 7-10%
of cases, including those in which previous routine cytogenetic testing has been normal (Sebat et al. (2007) Science
316(5823):445-449; Autism Genome Project Consortium et al. (2007) Nat Genet 39(3):319-328; Shen et al. (2010)
Pediatrics 125:e727-e735). The yield of CMA increases amongst individuals with complex autism (autism combined
with other health or developmental problems), with reports of abnormalities in up to 28% of cases of complex autism
(Jacquemont et al. (2006) J Med Genet 43(11): 843-849). Recently, the American College of Medical Genetics
professional practice guidelines recommended CMA as a “first line test” in the evaluation of individuals with autism
spectrum disorders (Manning and Hudgins (2010) Genet in Med 12(11): 742-745).

We have recommended chromosomal microarray analysis (CMA) for our patient [Patient Name] to determine
whether his autism/autism spectrum disorder is due to a submicroscopic gain or loss of chromosomal information.
CMA allows us to analyze the genome for gains or losses of genetic material at a much higher resolution than
standard karyotype analysis, and routinely identifies alterations that would be missed on standard blood
chromosome analysis.CMA has been shown to identify a pathogenic chromosomal alteration in approximately 710% of cases, including those in which previous routine cytogenetic testing has been normal (Sebat et al. (2007)
Science. 316(5823):445-449; Autism Genome Project Consortium et al. (2007) Nat Genet. 39(3):319-328; Shen et
al. (2010) Pediatrics. 125:e727-e735). Our recommendation for CMA is in keeping with the American College of
Medical Genetics’ professional practice guidelines, which has established CMA as a standard of care evaluation for
individuals with autism spectrum disorders (Manning and Hudgins (2010) Genet in Med 12(11): 742-745).
Multiple Congenital Anomalies

Congenital anomalies may be due to a genetic syndrome, chromosomal disorder, multifactorial condition, or may
be sporadic. In order to test [Patient Name] for common known genetic causes of congenital anomalies, we
recommend chromosomal microarray analysis (CMA). CMA analyzes the genome for gains or losses of genetic
material at a much higher resolution than standard karyotype analysis. CMA has the ability to detect small gains or
losses in genetic material that may have been missed on standard blood chromosome analysis alone. CMA is
considered standard of care in the evaluation of the individual with congenital anomalies by the American College of
Medical Genetics (Manning and Hudgins (2010) Genet in Med 12 (11): 742-745).
Prenatal - Ultrasound Anomalies and Normal Karyotype

In accordance with the American Congress of Obstetrics and Gynecology’s (ACOG) Committee Opinion #446,
which supports the use of chromosomal microarray analysis (CMA) in the setting of fetal abnormalities and a normal
fetal karyotype, we recommended CMA testing of [patient name]’s fetus (Obstet Gynecol. (2009) 114(5):1161-63).
CMA allows us to focus on known disease-associated regions within the genome, including all of the known
submicroscopic (i.e. not visible on high resolution karyotyping) microdeletion and microduplication syndromes, the
subtelomeres, and genome-wide coverage for the detection of other clinically significant regions that may lead to
mental retardation and/or additional health concerns.