CHRNG genotype–phenotype correlations in the multiple pterygium syndromes

• Published in: Journal of medical genetics Vol. 49; no. 1; pp. 21 - 26
• Main Authors: Vogt, Julie, Morgan, Neil V, Rehal, Pauline, Faivre, Laurence, Brueton, Louise A, Becker, Kristin, Fryns, Jean-Pierre, Holder, Sue, Islam, Lily, Kivuva, Emma, Lynch, Sally Ann, Touraine, Renaud, Wilson, Louise C, MacDonald, Fiona, Maher, Eamonn R
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Abnormalities, Multiple - diagnostic imaging; Abnormalities, Multiple - genetics; Abnormalities, Multiple - mortality; akinesia; arthrogryposis; Biological and medical sciences; CHRNG; clinical genetics; Cohort Studies; Confidence intervals; Congenital diseases; developmental; Diseases of eyelid, conjunctiva and lacrimal tracts; DNA Mutational Analysis; Escobar; Female; Fetal Growth Retardation - genetics; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Association Studies; genetic screening/counselling; genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Genotype & phenotype; Humans; Infant; Infant, Newborn; Malignant Hyperthermia - diagnostic imaging; Malignant Hyperthermia - genetics; Malignant Hyperthermia - mortality; Medical genetics; Medical sciences; Molecular and cellular biology; molecular genetics; Mutation; Nervous system; Ophthalmology; Pregnancy; pterygia; Pterygium - diagnostic imaging; Pterygium - genetics; Pterygium - mortality; Receptors, Nicotinic - genetics; Siblings; Skin Abnormalities; Studies; Ultrasonic imaging; Ultrasonography, Prenatal; Human; Pterygium; Eye disease; Correlation; Phenotype; Multiple; Typing; Genotype; Genetics; Conjunctiva disease
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2011-100378

BackgroundGermline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia.MethodsIn order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS.ResultsCHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies.DiscussionThe mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.