Cornelia de Lange Syndrome and Wiedemann-Steiner Syndrome via the KMT2A Gene

Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS (Deardorff et al. GeneReview, 2011).

KMT2A-related CdLS is inherited in autosomal dominant manner. Pathogenic KMT2A variants mainly cause Wiedemann-Steiner syndrome, which is characterized by hypertrichosis cubiti, short status, intellectual disability, and dysmorphic facial and skeletal features (Jones et al. 2012). The KMT2A protein (Histone-lysine N-methyltransferase 2A) coded by exons 1 to 36 of the KMT2A gene on 11q23.3 is a member of H3K4-specific methyltransferases that plays an essential role in early development and hematopoiesis (Shen et al. 2014). To date, approximately 15 unique pathogenic variants in KMT2A have been documented; most pathogenic variants were found in patients with Wiedemann-Steiner syndrome and only one de novo truncating pathogenic variant was reported in one patient with CdLS. The pathogenic variants include missense (4), nonsense (4), small del/ins (5), splicing (1) and large deletion (1). De novo pathogenic variants were found in five of the six Wiedemann-Steiner syndrome cases (Jones et al. 2012; Human Gene Mutation Database).

In one study, a de novo KMT2A pathogenic variant was found in one out of 32 Turkish patients clinically diagnosed with Cornelia de Lange syndrome (Yuan et al. 2015). In another study, de novo KMT2A pathogenic variants were found in five of the six Wiedemann-Steiner syndrome patients (Jones et al. 2012).

This test provides full coverage of all coding exons of the KMT2A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).