Know Your Genes

Individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are likely to have a change identified in the NIPBL gene. However, changes (or mutations) in NIPBL have been found in individuals with both classic and mild presentations. The degree of severity depends on the specific type of mutation that occurs and where the mutation falls within the NIPBL gene.

A truncating (or frameshift) mutation is one type of mutation that tends to have a more significant effect on the gene that can ultimately block protein production. Therefore, individuals with truncating mutations typically present with a more classic or severe form of CdLS.

Missense mutations are a different type of mutation which generally only slightly changes the protein. Therefore, individuals with missense mutations typically present with milder forms of CdLS, since their proteins likely retain some residual function.

Individuals with SMC1A or SMC3 mutations typically have fewer structural differences, such as a limb difference or heart difference. Such individuals also tend to present with less significant growth restriction than those with NIPBL mutations. However, individuals with SMC1A or SMC3 mutations will still typically have intellectual disability that can range from moderate to severe [Deardorff et al 2007].

Subtle facial features in individuals with SMC1A or SMC3 mutations may differ than those observed in “classic” CdLS caused by NIPBL mutations and can include slightly flatter and broader eyebrows with a broader and longer nasal bridge [Rohatgi et al 2010]. Specifically, individuals with SMC3 mutations often have subtle or absent synophyrs (connecting eyebrows), wider nose with a rounder tip, and a well-formed philtrum (vertical groove between the base of the nose and upper lip).

As broad-scale genetic testing has increased and many individuals with unexplained clinical findings are undergoing genetic testing, including exome sequencing (which sequences all 20, 000 genes in an individual to find answers), we have found some individuals to have changes or mutations in the SMC1A gene who do not have CdLS but rather have a severe seizure disorder with intellectual disability [Symonds et al., 2017]. The type of mutation affecting the SMC1A gene is what causes these different diagnosis. Individuals with CdLS caused by SMC1A mutations tend to have missense mutations that likely affect the function of the SMC1A protein whereas individuals with the severe seizures and intellectual disability tend to have mutations that likely knock out the function of the SMC1A protein completely. Since SMC1A is on the X chromosome (and boys have only one X chromosome and girls have two X chromosomes) we generally do not see boys with the severe seizure and intellectual disability clinical picture since they would have no functional SMC1A protein which would generally not be compatible with survival through embryonic development. We do see both males and females with SMC1A-related CdLS since the mutations in SMC1A that cause the CdLS diagnosis tend to result in an SMC1A protein being made but with decreased function than the non-mutated form.

Individuals with mutations in RAD21 typically do not have major structural differences. Individuals with RAD21 mutations have milder cognitive impairment compared to those with “classic” CdLS. These individuals typically display growth retardation, minor skeletal anomalies, and facial features that overlap with CdLS. [Deardorff et al 2012].

Individuals with mutations in HDAC8 have facial features which overlap with CdLS but typically display delayed closure of the anterior fontanel (the opening or “soft spot” on the top of the head in babies which typically closes around one year of age), hooded eyelids, a wider nose, varying pattern of skin pigmentation, and friendly personalities. Growth restriction also tends to be less significantly affected with this gene and a lower frequency of microcephaly (small head circumference) is reported.

In females, the severity of clinical presentation caused by mutations in HDAC8 is variable, since this gene is on the X chromosome and females have two X chromosomes while males have only one X chromosome and a Y chromosome. Since women have two X chromosomes in every cell, they randomly shut off one copy of the X chromosome (called X-inactivation). Therefore, depending on how many X chromosomes with the mutation versus those without the mutation are inactivated will directly influence the severity of their clinical presentation. (Though SMC1A is also located on the X chromosome this X-inactivation process does not apply to the SMC1A gene).

The BRD4 protein is known to interact with the NIPBL protein and mutations in the BRD4 gene have been recently reported in a few individuals with an atypical CdLS presentation [Kline et al. 2018]. The spectrum of clinical features associated with BRD4 is unclear with such few cases reported in the literature at this time [Olley et al. 2018]. However, from those that have been found to carry a BRD4 mutation, significant overlap with CdLS was noted. The key overlapping features observed in those with BRD4 mutations include intrauterine growth retardation (IUGR), global developmental delay, congenital heart defects (PDA, VSD, ASD), hearing loss, seizures, and gastroesophageal reflux. Overlapping facial features include synophrys, arched eyebrows, short nose and anteverted nostrils. Several findings atypical of classic CdLS reported in these individuals include normal height, preauricular ear tag, supernumerary nipple, hypothyroidism, hyperlipidemia, and a thin corpus callosum.

KBG syndrome is a neurodevelopmental disorder caused by mutations in the ANKRD11 gene. Some individuals with mutations in ANKRD11 have been reported to present with clinical features suggestive of Coffin-Siris syndrome or Cornelia de Lange syndrome. KBG syndrome is characterized by intellectual disability and/or developmental delays, characteristic facial features (triangular face, brachycephaly or a flatter appearing head, synophrys and hypertelorism or widely spaced eyes), large upper central incisors, skeletal anomalies, postnatal short stature, conductive hearing loss, and behavioral abnormalities (such as autism spectrum disorder or hyperactivity) [Swols et al. 2017]. Hearing loss is described in almost 1/3 of individuals with KBG and it can be conductive (CHL) or sensorineural hearing loss (SNHL). Some children can also have costovertebral anomalies (area where the ribs connect to the spinal column), scoliosis and EEG abnormalities with or without seizures. Behavioral difficulties such as hyperactivity, autistic features, aggressive compulsive behavior, and anxiety are also frequently observed. KBG can be quite variable in regard to cognitive abilities of affected individuals, and there have been no reported cases of regression in cognitive abilities. Like CdLS, most children will require support in the classroom, and special education. There have been over 100 cases of KBG syndrome reported, and while it is thought to be quite rare, it is likely undiagnosed due to the mild features present in some affected individuals. Studies suggest that males typically have more severe clinical presentations than females.