Cornelia de Lange Syndrome via the ANKRD11 Gene

Classic 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. 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. 2012). KBG syndrome is characterized by macrodontia of central upper incisors, mental retardation, dysmorphic facial features, short statue, skeletal anomalies and global developmental delay, seizures, and intellectual disability. KBG syndrome clinically overlaps with Cornelia de Lange syndrome (Ockeloen et al. 2015; Parenti et al. 2016). Cornelia de Lange syndrome is caused by pathogenic variants in 8 genes: NIPBL, SMC3, RAD21, SMC1A, HDAC8, KMT2A, AFF4, and ANKRD11.

ANKRD11-related CdLS and KBG syndrome are inherited in an autosomal dominant manner. The ANKRD11 protein belongs to the family of ankyrin repeat-containing cofactors that interacts with histone deacetylases to regulate gene expression. Almost 50 pathogenic variants have been reported, mainly found in patients with KBG syndrome. Most of these variants are truncating caused by nonsense variants or frameshifts. Missense and splice variants are rare. Large deletions/duplications account for ~30% of reported pathogenic variants (Human Gene Mutation Database). Only 4 unique, pathogenic variants were reported in patients affected with CdLS, all de novo, truncating variants (Ansari et al. 2014; Parenti et al. 2016).

Clinical sensitivity is high for patients with KGB syndrome. For example, in one study, sequencing analysis identified an ANKRD11 pathogenic variant in 12 out of 13 studied KGB families (Ockeloen et al. 2015). ANKRD11 pathogenic variants were only identified in a few CdLS patients who did not have pathogenic variants in NIPBL, SMC1A, SMC3, HDAC8 and RAD21 (Ansari et al. 2014; Parenti et al. 2016).

Large deletions/duplications account for ~30% of reported variants in ANKRD11 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ANKRD11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.