Presentation: Infant with congenital malformation and dysmorphism syndrome

A four-week-old infant has been an inpatient since birth for management of choanal atresia and omphalocele diagnosed postnatally. Further evaluation has revealed small ears, a coloboma, a large ventricular septal defect and right-sided hydronephrosis.

• Genomic testing should be considered in the presence of facial dysmorphism, either alone or in combination with any congenital malformation (such as limb defects or organ abnormalities).
• The following clinical features may be the result of teratogenic exposure or may be of multifactorial inheritance, with interactions between genetic and environmental factors. However, combinations of these congenital anomalies with or without dysmorphic features should prompt potential genomic evaluation:
  • neural tube defects;
  • anencephaly or microcephaly;
  • cleft lip or palate;
  • gastroschisis;
  • gastrointestinal anomalies (such as oesophageal or intestinal atresia or stenosis, anorectal anomalies or a tracheoesophageal fistula);
  • diaphragmatic hernia, particularly if associated with cleft lip or palate or cardiac, central nervous system, renal or bone anomalies; and/or
  • urogenital anomalies.
• Congenital anomalies affecting multiple family members should increase the suspicion of an underlying genetic cause.

Terminology: A malformation is defined as any structural defect arising from an intrinsically abnormal developmental process (for example, a cleft lip). Deformations are physical anomalies arising from mechanical force (for example, a club foot). Disruptions represent physical interruption or destruction of tissue that was normal during fetal life (for example, duodenal atresia secondary to vascular insufficiency).

Therefore, malformations should be differentiated from both deformations and disruptions which have a lower chance of being associated with an underlying genetic condition.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• 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. For congenital malformations and/or dysmorphism, there are a number of available panels, including:
  • R26 Likely common aneuploidy: This should be performed first where aneuploidy (trisomy 13, trisomy 18 or trisomy 21) is considered to be the most likely diagnosis (send lithium heparin samples, alongside EDTA, in case a karyotype is required);
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: This should be considered if there are clinical features suggestive of a specific chromosomal cause (such as 22q11 deletion or Williams syndrome). Where possible, the chromosomal disorder suspected should be specified on the test request form;
  • R14 Acutely unwell children with a likely monogenic disorder: This expedited test utilising whole genome sequencing (WGS) should be considered for patient who are acutely unwell, there is a likely monogenic disorder, and molecular diagnosis is likely to imminently alter management. Requesting R14 usually requires authorisation from clinical genetics.
  • R27 Paediatric disorders: This should be considered if there are congenital malformations and/or dysmorphism. Testing of adults with congenital malformation and dysmorphism syndromes would also be appropriate under this clinical indication. Additional panels relevant to the patient phenotype can also be added.
• There are some conditions with unusual mechanisms that may be missed by WGS. Examples include some mitochondrial disorders, triplet repeat disorders and methylation disorders.
  • Investigation for disorders of methylation may be appropriate when there is a high degree of clinical suspicion of the following conditions:
    • R47 Angelman syndrome: methylation testing and multiplex ligation-dependent probe amplification (MLPA);
    • R48 Prader-Willi syndrome: methylation testing and MLPA; and
    • R49 Beckwith-Wiedemann syndrome: methylation testing, MLPA and single gene sequencing.
• For tests that do not include WGS, including R26, R28, R47, R48 and R49:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, 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).
• R27 is a large WGS super panel (a panel comprised of several different constituent panels forming one large panel). R27 may be ordered directly by paediatricians, though discussion with clinical genetics may be beneficial in some cases.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics. There is a special test order form and RoD form for this test, both of which are available from the Exeter Genetics Laboratory.
• Most 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). For more information, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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.

For clinicians

• NHS England: National Genomic Test Directory
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource

For patients

• Unique (Support for families of children with rare chromosome and gene disorders.)
• Syndromes without a name (SWAN) (Support group for families without an underlying diagnosis.)