Multiple Pterygium Syndrome via the CHRNG Gene

Like fetal akinesia deformation sequence, multiple pterygium syndrome may be caused by impaired intrauterine movement secondary to abnormalities in proteins at the neuromuscular junction. Lethal multiple pterygium syndrome (LMPS, OMIM 253290) is characterized by prenatal growth deficiency, contractures, pterygia, and dysmorphic facies. Joint contractures and multiple pterygia are universal findings. Patients are stillborn or do not survive beyond the newborn period. Pulmonary hypoplasia is likely the primary cause of mortality. Contractures are found at the elbows, knees, hips, shoulders, hands, and feet. Pterygia are found between the chin and sternum as well as the popliteal, axillary, antecubital, and ankle areas. Facial features include ocular hypertelorism, epicanthal folds, small chin and mouth, and low-set ears. Patients commonly are born with hydrops and pregnancies are affected with polyhydramnios. Escobar syndrome or Escobar variant of multiple pterygium syndrome (OMIM 265000) has clinical features that are similar to but milder than LMPS. Patients have normal intelligence and most are able to walk. Pterygia occur at the neck, axillae, popliteal, antecubital, and intercrural areas. Facial features include ptosis, hypertelorism, small chin and mouth, long philtrum, and low-set ears. Patients may have difficulty opening their mouths widely and exhibit an emotionless facial appearance. Other findings include camptodactyly, syndactyly, club feet, and hypoplastic genitalia. Respiratory complications resulting from scoliosis and kyphosis may occur.

Abnormalities of proteins involved with neuromuscular transmission underlie multiple pterygium syndromes, congenital myasthenia syndromes, limb girdle myasthenia syndrome, and Pena-Shokeir syndrome. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. Variants in CHRNG cause both LMPS and Escobar syndrome (Hoffman et al. Am J Hum Genet 79:303-312, 2006; Morgan et al. Am J Hum Genet 79:390-395, 2006). CHRNA1 and CHRND variants also underlie LMPS (Michalk et al. Am J Hum Genet 82:464-476, 2008). CHRNG encodes the gamma subunit of the acetylcholine receptor which is expressed only during fetal development. The mature acetylcholine receptor contains the epsilon subunit in place of the gamma subunit.

Analytical sensitivity should be high because the variants reported are readily detectable by gene sequencing. Clinical sensitivity may be low because fetal akinesia has multiple underlying causes including environmental, immunological, and genetic.

This test provides full coverage of all coding exons of the CHRNG gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).