Inspired by a patient
Hempel M, Cremer K, Ockeloen CW, Lichtenbelt KD, Herkert JC, Denecke J, Haack TB, Zink AM, Becker J, Wohlleber E, Johannsen J, Alhaddad B, Pfundt R, Fuchs S, Wieczorek D, Strom TM, van Gassen KL, Kleefstra T, Kubisch C, Engels H, Lessel D. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment. Am J Hum Genet. 2015 Sep 3;97(3):493-500.
CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.
From the article
Taken together, all five individuals with a de novo deleterious CHAMP1 mutation are affected by ID[intellectual disability] and delayed motor development with a particularly severe delay in speech development. Whereas the motor development improved over time, speech impairment remained. All individuals suffered from muscular, in particular truncal, hypotonia. Orofacial hypotonia was observed in four probands. Similar dysmorphic features, including a short philtrum, tented upper lip, and everted lower lip were observed in all individuals. Three individuals presented with upslanting palpebral fissures, low-set ears, and a long face and pointed chin. A friendly behavior was described in all individuals. Decreased pain sensation, feeding difficulties during the neonatal period, hyperopia, and a high arched palate were noted in four individuals. Three individuals displayed stereotypic movements. Three individuals showed microcephaly. Before identifying the causative CHAMP1 mutations, a number of different specific genetic tests had been performed. The most important genetic differential diagnoses were Prader-Willi (PWS) and Angelman syndromes (AS). PWS was suspected in three probands because of feeding difficulties. At toddler age, the severely delayed speech development, the microcephaly, and ataxic gait made Angelman syndrome an important differential diagnosis, which was tested in three probands. ARX analysis was performed because of ID and speech delay in two male probands…
The findings in altogether seven independent individuals thus confirm that mutations in CHAMP1 are a monogenic cause of ID/GDD. In line with this assumption, there is no single loss-of-function CHAMP1 variant deposited in the ExAC database, including more than 110,000 sequenced alleles at this locus, which argues strongly for a deleterious effect of CHAMP1 mutations. Notably, the Residual Variation Intolerance (RVI) score, which quantifies gene intolerance to functional mutations7 of CHAMP1, is −0.75 (13.71th percentile) and thus even lower than the average RVI score for genes involved in developmental disorders (0.56; 19.54th percentile). This suggests that the degree of intolerance to deleterious variants of CHAMP1 is significantly more pronounced than the average degree of intolerance to deleterious variants of genes known to have mutations that cause developmental disorders.
CHAMP1 is located at chromosome 13q34 and contains a single coding exon (as well as two 5′-untranslated exons) encoding for a zinc-finger protein of 812 amino acids. CHAMP1 was shown to interact with the mitotic control protein MAD2L2 and is required for its spindle localization. CHAMP1 localizes to chromosomes and the mitotic spindle and regulates localization of CENPE and CENPF to kinetochores. Furthermore, it regulates kinetochore-microtubule attachment and therefore proper chromosome alignment.5 Mutations affecting genes encoding for proteins that regulate chromosome alignment and/or spindle assembly are a well-established cause of a variety of syndromic and non-syndromic developmental disorders.