Developmental Delay: Genetic Testing’s Role to Help Guide Diagnosis and Treatment

Kosofsky, Barry, MD, PhD
Professor of Pediatrics and Chief, Division of Pediatric Neurology
New York-Presbyterian Hospital/Weill Cornell Medical Center
Director, Horace W. Goldsmith Foundation Laboratory of Molecular and Developmental Neuroscience
New York, New York Also by this Author 

Causes of developmental delay are typically identified by a combination of observation, physical examination, assessment of family history and a range of diagnostic tests. For disorders of uncertain etiology, chromosomal microarray (CMA) testing provides clinicians with an additional diagnostic tool, and is recommended by the American College of Medical Genetics (ACMG) as a first-line genetic test for developmental delay, intellectual disability, autism spectrum disorders and multiple congenital anomalies.1

Dr. Barry Kosofsky, Goldsmith Professor of Pediatrics and Chief, Division of Pediatric Neurology, New York-Presbyterian Hospital/Weill Cornell Medical Center discusses the role of CMA in diagnosing certain developmental disorders, assessing prognosis and guiding therapy.

Identifying Developmental Delay – A Triage Approach

Dr. Kosofsky explains that the diagnosis of developmental disorders typically follows a triage approach. This begins with parental observation and concern, followed by visits to the pediatrician and referral to a sub-specialist. “Pediatricians are equipped with a number of surveillance questions to ask, as well as appropriate milestones to discuss, at each visit,” he says. “If there's a concern they can implement one of the standard tools, such as the Denver Developmental Assessment, which is divided into different domains of functioning, including fine motor, gross motor, personal social, and language skills.” These screens are helpful in separating delay into domain-specific versus global problems. For example, children with cerebral palsy have worse fine motor delay than gross motor delay, children with autism have more personal, social and language deficits, and children with Down syndrome would have a global delay that would equally affect each of those different domains. There are also more specific screens, such as the CARS assessment for autism.        

Referral to a Sub-Specialist

Once the pediatrician has identified that a child lies outside of acceptable development, a referral will be made to a sub-specialist - a geneticist, child neurologist or developmental pediatrician, depending upon the pediatrician’s assessment. Referral will be to a geneticist if a family history indicates a condition is heritable, or if certain physical features, dysmorphic features, indicate a child may have a genetic syndrome.    

Referral will be made to a child neurologist based on one of various factors: a history of seizures or of focal deficits; an abnormality on the neurologic examination; if the child demonstrates low tone (i.e. floppy) or increased tone (i.e., stiff); the head circumference is either too big or too small for age.  In the third case, where there are no apparent genetic or syndromic factors, or no focal or other abnormalities on examination, the referral may be to a developmental pediatrician.          

The sub-specialist will then perform the appropriate set of tests.  For a neurologist this may include an MRI and/or an EEG depending on the child’s history and physical evaluation. The developmental pediatrician will often refer the child to what is termed an “early intervention team”, which consists of a team of occupational therapists who look at fine motor coordination, physical therapists who look at gross motor coordination and balance, and speech and language therapists who look at language development. This evaluation will lead to recommendations regarding the optimizing of services, and may lead to referral to a geneticist or child neurologist.

Chromosomal Microarray (CMA) Testing – Efficient and Cost-Effective

If there’s a suspicion of genetic factors, the geneticist or child neurologist may order a genetic test. “If there's a family history of a genetic problem or something that fits a specific pattern, you can do targeted analysis for a particular chromosomal abnormality,” notes Dr. Kosofsky. ”This would be the case for Fragile X syndrome, Prader-Willi syndrome or Down syndrome. In recent years, however, testing has become more sophisticated and we would now routinely order a chromosomal microarray.  This is highly sensitive in picking up DNA insertions or deletions, which are also known as copy number variants (CNV). It's been shown these tests can detect 98% of genetic syndromes,1, 2 so this has revolutionized our approach. Instead of trying to guess what the specific mutation is and sending a single test, we can send a more comprehensive test that will pick up 98% of known genetic abnormalities.”

“Combined with the chromosome tests,” continues Dr. Kosofsky, ”microarray testing is now recommended by all the key organizations: the American Academy of Pediatrics, the American College of Medical Genetics, the Child Neurology Society, and the American Academy of Neurology.3 Everybody has realized in the last 10 years that this approach increases efficiency.” 

One challenge for clinicians is interpreting the presence of copy number polymorphisms (CNPs), and determining whether or not a specific variant identified in the genome of a child is acceptable. “In this situation, the clinician who has sent the array needs to get an interpretation of the result, which a good laboratory will provide,” notes Dr. Kosofsky. “If the result is positive the laboratory will provide a consultation with a genetic counselor, who will advise if that polymorphism is associated with a disease or if it’s a variant that has not been established as being clinically relevant.”

Genetic Testing of Parents

If a CNV that’s considered relevant is identified, the physician will test the parents to see whether or not they have that abnormality. This is done in a focused way at the specific site of the genome where there is concern to confirm or refute whether the parent has that abnormality. If the parent has the abnormality and is normal, that genetic variant is less likely to be causing the disease.  If the parents don't have that abnormality, then it is more suspicious, especially if it's a genetic variant that's been associated previously with disease.

The child neurologist also has to address diagnostic challenges presented by metabolic disorders and epileptic disorders. Suspicion that one of these disorders may be present is increased if a child appears to exhibit developmental regression, notes Dr. Kosofsky. “We distinguish between static and progressive disorders,” he says. “A lot of the genetic disorders are static, meaning that your brain or body didn't form correctly leading to a deficit, but not one that results in a loss of skills previously acquired. Abnormality in a gene central to metabolism, however, could lead to a regression of skills.  Based on the assessment, the child neurologist can order various tests, such as amino acids, organic acids or acylcarnitine, to determine the nature of the metabolic disease and potential therapy.”  The need for some of this testing is mitigated by stat screens for disorders such as Phenylketonuria (PKU) or hypothyroidism.  If these screens were performed at birth the clinician will need to confirm that they were normal and thereby exclude some of the more common metabolic abnormalities.        

Genetic Testing – Helping Establish Diagnosis, Prognosis and Therapy

Genetic testing helps clinicians address what Dr. Kosofsky describes as the two pieces of the developmental disorder puzzle: diagnostics and therapeutics. “The advantage of making a genetic diagnosis is that you can confirm a particular syndrome or type of epilepsy,” he says.  “This often gives an insight into the natural history of the disease and so allows the physician to provide the family with a sense of the prognosis.  A genetic diagnosis also helps identify which medications are likely to be most effective, in particular for the epilepsies, and can guide treatment decisions.” 

Genetic testing can also help assess the risk of recurrence - the likelihood of having this kind of abnormality in a subsequent pregnancy - or the implications of somebody in the family being asymptomatic or a carrier. “The carrier status has implications for their children,” says Dr. Kosofsky, “though certain genetic abnormalities affect some children more than others. So, you would have a sense of whether or not other children needed to be watched more carefully.”          

Advances on the Horizon

Dr. Kosofsky foresees significant advances in the field of genetic testing. “ Research is moving remarkably quickly in this area,” he notes. “For example, in 10 to 15 years we hope to be using tests based on exome sequencing, sequencing the 1% of the human genome that codes for the proteins that we are made of. Right now this is still in the research arena, but I anticipate it will become like microarrays today, providing even greater sensitivity to detect subtle genetic abnormalities.  Work is progressing in specific areas like epilepsy and neurodegenerative disorders. As more diseases are identified, and more confirmations are made regarding acceptable versus disease-causing variants, I think exome sequencing will become one of the central genetic diagnostic tools of the future.”


  1. Miller D1, Adam M, Aradhya S, Biesecker L, Brothman A et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749-64. doi: 10.1016/j.ajhg.2010.04.006.
  2. Wapner R, Lese Martin C, Brynn Levy B, Ballif B, Eng C, Zachary J, Savage M.  Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis. N Engl J Med. 2012;367:2175-84. DOI: 10.1056/NEJMoa1203382
  3. Saty Satya-Murti S,  Cohen B,  Michelson D. Chromosomal Microarray Analysis for Intellectual Disabilities. American Academy of Neurology Accessed April 25, 2014

Released on Friday, May 09, 2014