​Southeast Asia's first accredited choromosomal microarray analysis laboratory aids diagnosis of genetic disorders in babies and children.

This article was first published in KKH Special Delivery Mar-Apr 2015 issue.

KK Women’s and Children’s Hospital (KKH) has launched Southeast Asia’s first accredited chromosomal microarray analysis (CMA) diagnostic test, to aid the diagnosis of genetic disorders in babies and children.

Chromosomal microarray analysis (CMA), a DNA-based method of genetic investigation, helps to identify clinically significant chromosome anomalies that are too small to be detected by conventional chromosome analysis – also known as karyotyping.

“With an expected diagnostic yield of about 20 percent, compared with 3.7 to 9.5 percent for conventional karyotyping, CMA is expected to provide an underlying genetic diagnosis in a greater proportion of patients,” says Dr Angeline Lai, Head and Senior Consultant, Genetics Service, KKH, who leads the CMA diagnostic service.

“This benefits patients as it ends the diagnostic odyssey, preventing further unnecessary investigations.   It also provides information about possible complications, allowing appropriate monitoring and early management, and facilitates the provision of accurate information about recurrence risks in future pregnancies, and the reproductive choices available.”

Decoding the genetic cause of childhood disorders

Since its launch in February 2014, the hospital has performed CMA diagnostic testing for 143 patients comprising mainly babies and children.   Twenty-nine (20%) were identified to have copy number variants – deletions and duplications of chromosomal segments – that were pathogenic (known to cause disease) or likely pathogenic.

These led to the eventual diagnosis of 24 genetic syndromes, most common of which were Angelman/Prader-Willi syndrome (4), Velocardiofacial syndrome (2) and 1p36 microdeletion syndrome (2).

• Microdeletions of chromosome 15 at bands q11.2q13 cause Angelman syndrome or Prader-Willi syndrome, depending on whether the deletion occurs on the maternal or paternal copy of chromosome 15.

• Angelman syndrome is characterised by developmental delay or intellectual disability, unsteady gait, frequent laughter/ smiling and seizures. 

• Prader-Willi syndrome in babies is characterised by low muscle tone (hypotonia), distinct facial features, feeding difficulties and developmental delay. Older children with Prader-Willi syndrome may have excessive appetites, leading to obesity if uncontrolled. 

• Velocardiofacial syndrome, caused by a microdeletion at chromosome 22q11.2, is characterised by a combination of medical problems that vary from child to child. More common characteristics include cleft or other problems in the palate, heart defects, problems fighting infection and speech and feeding problems. 

• 1p36 microdeletion syndrome in babies is characterised by low muscle tone, seizures, developmental delay and brain or heart abnormalities.

To enable patients to make an informed choice about testing, information about CMA is provided to patients and their families, and their consent is obtained prior to the test being performed. Pre-test counselling informs patients about the benefits and limitations of CMA testing, as well as the possibility of obtaining a result of uncertain clinical significance.

Where testing yields an abnormal result, genetic counselling is recommended to explain the findings and any diagnosis made, as well as to plan appropriate intervention and management.

The CMA diagnostic service is a joint collaboration between several hospital services at KKH: the SAC-SINGLAS*-accredited Cytogenetics Laboratory (Department of Pathology and Laboratory Medicine) and DNA Diagnostic and Research Laboratory; the Genetics Service (Department of Paediatrics); and KK Research Laboratory.

* Singapore Accreditation Council Singapore Laboratory Accreditation Scheme (SAC-SINGLAS)

What are chromosome anomalies? 

Chromosome anomalies include deletions, duplications and other alterations in whole or parts of chromosomes.

Either inherited or occurring spontaneously, chromosome anomalies are estimated to be present in one in 150 babies, and are implicated in 25 percent of all miscarriages and stillbirths, and 50 to 60 percent of miscarriages in the first trimester.

They are the underlying cause in a substantial proportion of conditions that present at birth or during childhood.   These include multiple congenital anomalies (MCA), developmental delay and/or intellectual disability (DD/ID), and autism spectrum disorder (ASD).

The American College of Medical Genetics recommends CMA as first-tier genetic testing for patients with these disorders.

CASE STUDY:
CMA diagnosis of 15q24 microdeletion syndrome in an adolescent female

Patient P was first seen by the Genetics Service at KKH in 2004, at the age of two.  She presented with failure to thrive, hypotonia, global developmental delay and non-specific dysmorphic features.

Investigations carried out included blood tests to analyse her muscle enzymes, computed tomography of the brain and conventional karyotyping – all of which yielded normal results.   Patient P’s family had no history of congenital disorders, and her only other sibling was well.   The patient was referred for early intervention to support her developmental needs, and the family subsequently discontinued follow-up visits to the hospital.

In 2014, patient P presented to the hospital with acute abdominal pain and vomiting. Investigations revealed a severe hiatal hernia – protrusion of the upper stomach through the diaphragm – for which she subsequently underwent surgical repair.   During patient P’s hospitalisation, her parents reported that she had been receiving special education and progressing in her development.   At 12 years of age, she was able to carry out self-care tasks independently and communicate in sentences.

With informed parental consent, patient P underwent CMA, and results revealed a pathogenic loss of 3.96 Mb at 15q24.1q24.3.   This is consistent with a diagnosis of 15q24 microdeletion syndrome –in which a small piece of chromosome 15 is deleted in each cell.

Through CMA, the hospital care team was able to make an accurate genetic diagnosis for patient P, and provide genetic counselling to her family on specific recurrence risks and reproductive choices.

About 15q24 microdeletion syndrome
15q24 microdeletion syndrome is characterised by dysmorphic facial features, developmental delay, hypotonia, digital and genital abnormalities, and diaphragmatic hernia – most of which were present in patient P. Reported cases of the syndrome have all arisen as spontaneous microdeletions, and the recurrence risk for parents is expected to be low