Molecular dissection of CHARGE syndrome highlights the vulnerability of neural crest cells to problems with alternative splicing and other transcription-related processes

Figures & data

Figure 1. Potential mode of action of Fam172a in Ago2-mediated alternative splicing. Although the relationship between all players shown remains to be characterized in detail, current data suggest that the presence of Fam172a at the chromatin-spliceosome interface helps stabilizing protein-protein interactions between the small-RNA binding protein Ago2, chromatin remodelers such as Chd7 and histone modifiers such as Ehmt2. Model adapted from Refs [22,24].

Table 1. Clinical and molecular overlap between CHARGE syndrome and other rare conditions.

Pathology	Clinical characteristics*	Causative Gene(s)
CHARGE syndrome (OMIM #214,800)	Brain (e.g. corpus callosum agenesis, olfactory bulb hypoplasia microcephaly) Cardiac (e.g. septal defects, patent ductus arteriosus, Tetralogy of Fallot) Cranial nerves (e.g. facial palsy, swallowing difficulties) Craniofacial (e.g. square face, flat midface, facial asymmetry, downslanting palpebral fissures) Ears (e.g. small and cup-shaped external ears, hypoplastic semi-circular canals) Eyes (e.g. coloboma, microphthalmia) Genitourinal (e.g. cryptorchidism, hypogonadotropic hypogonadism, uterus agenesis, kidney hypoplasia) Growth retardation and intellectual disability Immunological (e.g. thymus hypoplasia, immunodeficiency) Oronasal (e.g. choanal atresia, cleft palate/lip) Sensorineural (anosmia, hearing loss) Skeletal (e.g. scoliosis, limb and hand anomalies) Laryngopharyngeal (e.g. tracheoesophageal fistula, parathyroid hypoplasia)	Chromatin factors CHD7(major), EP300, KMT2D, KDM6A (uncertain) Chromatin-spliceosome interface FAM172A Splicing factors PUF60, EFTUD2 (uncertain) Transcription factors RERE Other SEMA3E (uncertain)
22q11.2 syndrome (OMIM #188,400)	Cardiac (e.g. septal defects, patent ductus arteriosus, Tetralogy of Fallot) Craniofacial (e.g. telecanthus, short palbebral fissure, micrognathia, square nasal tip) Ears (e.g. low-set and abnormally-folded external ear) Growth retardation and intellectual disability Immunological (e.g. thymus hypoplasia) Oronasal (e.g. small mouth, cleft palate) Laryngopharyngeal (parathyroid hypoplasia) Sensorineural (hearing loss)	Transcription factors TBX1(major)
Acrofacial dystosis 1, Nager type (OMIM #154,400)	Craniofacial (micrognathia, malar hypoplasia, downslanting palpebral fissures, midface retrusion) Ears (e.g. small and abnormally-folded external ear) Eyes (e.g. eyelid coloboma) Oronasal (e.g. cleft palate/lip) Sensorineural (hearing loss) Skeletal (e.g. limb and hand anomalies)	Splicing factors SF3B4 (major), EFTUD2 (uncertain)
Kabuki syndrome (OMIM #147,920, 300,867)	Brain (e.g. microcephaly) Cardiac (e.g. septal defects, patent ductus arteriosus, Tetralogy of Fallot) Craniofacial (e.g. long palpebral fissures, arched eyebrows, broad and depressed nasal tip, dental agenesis) Ears (e.g. large and abnormally-folded external ears) Eyes (e.g. strabismus) Genitourinal (e.g. early puberty) Growth retardation and intellectual disability Immunological (e.g. immune deficiency) Oronasal (e.g. cleft palate) Skeletal (e.g. scoliosis, limb and hand anomalies)	Chromatin factors KMT2D (major), KDM6A
Kallmann syndrome (OMIM #308,700, 147,950)	Brain (e.g. olfactory bulb hypoplasia) Craniofacial (e.g. dental agenesis) Genitourinal (e.g. cryptorchidism, hypogonadotropic hypogonadism, kidney agenesis) Growth retardation and intellectual disabillity Oronasal (e.g. cleft palate/lip) Sensorineural (anosmia, hearing loss)	Chromatin factors CHD7 Other FGFR1 (major),FGF8, KAL1, PROKR2, GNRH
Mandibulofacial dystosis, Guion-Almeida type (OMIM #610,536)	Brain (e.g. microcephaly) Cardiac (e.g. septal defects, patent ductus arteriosus) Craniofacial (midface and malar hypoplasia, micrognathia, oblique palpebral fissure) Ears (e.g. low-set and abnormally-folded external ears, preauricular tags, inner ear malformations, conductive hearing loss) Laryngopharyngeal (e.g. tracheoesophageal fistula) Growth retardation and intellectual disabillity Oronasal (e.g. choanal atresia, cleft palate)	Splicing factors EFTUD2

*Note: all these characteristics do not usually co-occur in a given patient

Belanger C, Berube-Simard FA, Leduc E, et al. Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E620–E629. PubMed PMID: 29311329; PubMed Central PMCID: PMC5789929.

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Ameyar-Zazoua M, Rachez C, Souidi M, et al. Argonaute proteins couple chromatin silencing to alternative splicing. Nat Struct Mol Biol. 2012 Oct;19(10):998–1004. PubMed PMID: 22961379.

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