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Cornelia de Lange Syndrome Panel

May 23, 2018

Disease summary:

Cornelia de Lange syndrome (CdLS) is a rare inherited multisystem developmental disorder characterized by distinctive craniofacial features, growth retardation with prenatal onset, intellectual disability, limb malformations, hirsutism, sensorineural hearing loss, myopia, nystagmus and cryptorchidism1, 7, 8, 9, 11.

CdLS is caused by pathogenic variants in genes responsible for the formation and regulation of the cohesin complex (genes: HDAC8, NIPBL, RAD21, SMC1A, SMC3)2, 3, 4-12. Cohesin is a chromosome-associated multisubunit protein complex that mediates cohesion between replicated sister chromatid and is essential for chromosome segregation in dividing cells. 

Autosomal dominant

1/100,000 2 to 1/10,000 3

Classical CdLS symptoms in >95% of individuals 1:

  • Distinctive craniofacial features
    • Microbrachycephaly
    • Synophrys
    • Low-set posteriorly rotated ears
    • Depressed or wide nasal bridge, upturned nasal tip with anteverted nares
    • Long and smooth philtrum
    • High and arched palate with/without cleft
    • Small widely-spaced teeth
    • Micrognathia
    • Short neck

  • Growth failure prenatally
  • Severe to profound intellectual disability
  • Limb abnormalities (severity ranging from absence of upper limbs to oligodactyly)
  • Hirsutism
  • Other symptoms:
    • Psychiatric and behavioral problems
    • Seizures (~25% of affected).
    • Temperature intolerance and decreased pain sensation.
    • Gastroesophageal reflux.
    • Pyloric stenosis (~ 4% of newborns). 

Presence of the specific clinical features

Identification of a heterozygous pathogenic variant in one of the following genes (Table 1): AFF4, HDAC8, KMT2A, NIPBL, RAD21, SMC1A, SMC3, TAF6.

Treatment of Cornelia de Lange syndrome is only symptomatic and it most commonly includes the following 1:

  • Physical, occupational, and speech therapy
  • Management of  GE reflux, if present
  • Supplementary formulas and/or gastrostomy tube placement, if failure to thrive).
  • Standard treatment for hearing loss, cardiac defects, seizures, vesicoureteral reflux, and cryptorchidism.
  • Partial duplication of 3q
  • Deletions of chromosome 2q31
  • Fryns syndrome caused by several different chromosome aberrations
  • Fetal alcohol syndrome (FAS)
  • X-linked intellectual disability syndrome caused by TAF1 pathogenic variants
  • Bohring-Opitz syndrome caused by a heterozygous pathogenic variant in ASXL1

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Cornelia de Lange syndrome using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cornelia de Lange syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step 1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of Cornelia de Lange syndrome
  • Individuals with most common symptoms of Cornelia de Lange syndrome (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of Cornelia de Lange syndrome can allow for genetic counseling and may direct medical management.