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Example clinical scenario

A term baby is admitted at day one to the neonatal unit because she is profoundly floppy (hypotonic). There are no other dysmorphic features or congenital anomalies, and she is spontaneously ventilating in air.

When to consider genomic testing

Genomic testing should be considered if:

  • an infant is assessed as having significant hypotonia;
  • hypotonia is not attributed to an acquired cause (such as sepsis or hypoxic encephalopathy);
  • the infant has additional medical problems and/or dysmorphic features;
  • an older child with hypotonia is alert and interactive, in which case you should consider neuromuscular causes; or
  • an older child is not alert, or has a developmental delay, in which case you should consider central causes.

Specific conditions or families of conditions that can present with hypotonia include:

In many instances, the specific underlying genetic diagnosis for a hypotonic infant may be unclear.

For the acutely unwell infant, please see Presentation: Child acutely unwell in NICU or PICU.

What do you need to do?

  • Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Decide which of the panels best suits the needs of your patient or family.
    • If you suspect a common trisomy (such as trisomy 21, 18 or 13):
      • R26 Likely common aneuploidy: This is genome-wide common aneuploidy testing (send EDTA and lithium heparin samples).
    • If you suspect a wider chromosomal disorder:
      • R28 Congenital malformation and dysmorphism syndromes – microarray only: This is a genome-wide microarray.
    • If you suspect Prader-Willi syndrome:
    • If you suspect a likely central cause:
      • R69 Hypotonic infant: For where there’s likely a central cause. This is a multifaceted test and is subdivided as follows:
        • R69.3 Genomewide Microarray: Uses microarray to investigate copy number variants (chromosome deletions or duplications);
        • R69.5 Hypotonic infant W: Whole genome sequencing (WGS) to investigate for single gene variants;
        • R69.6 Hypotonic infant STR confirmatory testing: This is short tandem repeat (STR) testing for congenital myotonic dystrophy
    • If you suspect SMA:
      • R70 Spinal muscular atrophy type 1 diagnostic test: SMN1 multiplex ligation-dependent probe amplification (MLPA) or equivalent to assess SMN1 gene dosage. This test should be performed first as most individuals with SMA have deletions of both copies of the SMN1 gene.
      • R71 Spinal muscular atrophy type 1 rare mutation testing: SMN1 gene testing. This test is for individuals with a clinical diagnosis of SMA where only one copy of the SMN1 gene is deleted. The test looks for a sequence variant on the other allele.
    • If you suspect a broader multi-system condition due to the presence of congenital anomalies and/or dysmorphic features alongside hypotonia:
      • R27 Paediatric disorders: This is a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
    • If a neonate or child with significant hypotonia is acutely unwell, likely to have a monogenic disorder and a molecular diagnosis is likely to impact management:
      • R14 Acutely unwell children with a likely monogenic disorder: Rapid WGS agnostically across the genome.
        • R14 requests currently require authorisation from clinical genetics.
        • There is a special test order form and Record of Discussion (RoD) form for this test, which are available from the Exeter Genetics Laboratory.
  • For tests that are undertaken using WGS, including R27 and R69, you will need to:
    • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
    • complete an NHS GMS RoD form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
    • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
  • For tests that do not include WGS, including R26, R28, R48, R70 and R71:
    • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
    • parental samples may be needed for interpretation of the infant’s result. Parental samples can be taken alongside that of the infant, and their DNA stored, or can be requested at a later date if needed.
  • The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

References:

  • Sparks SE. ‘Neonatal hypotonia’. Clinical Perinatology 2015: volume 42, issue 2, pages 363–371. DOI: 10.1016/j.clp.2015.02.008

For patients

  • National Institute of Neurological Disorders and Stroke: Hypotonia
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  • Last reviewed: 29/09/2024
  • Next review due: 29/09/2025
  • Authors: Dr Lianne Gompertz
  • Reviewers: Dr Eleanor Hay, Dr Emile Hendriks