Congenital Myasthenic Syndromes and Multiple Pterygium Syndrome via the CHRND Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or postsynaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness. Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running. Most patients present prior to 2 years of age although rare exceptions are reported (eg. Croxen et al. Neurol 59:162-168, 2002). Symptoms are extremely variable and are in some cases induced by febrile illness, infection, or excitement (eg. Byring et al. Neuromuscul Disord 12:548-553, 2002). Life-threatening respiratory crises may occur in affected neonates or older children. CMS may be differentiated from myasthenia gravis, an acquired autoimmune disorder, by earlier age at onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies. 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. 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.

Abnormalities of proteins involved with neuromuscular transmission underlie CMS, limb girdle CMS, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. CHRND gene variants have been found in patients with fast and slow channel CMS (Engel and Sine Curr Opinion in Pharmacol 5:308-321, 2005). Fast channel CMS (OMIM 608930) secondary to loss-of-function variants in the acetylcholine receptor delta gene (CHRND, OMIM 100720) is inherited as a recessive condition (Brownlow et al. J Clin Invest 108:125-130, 2001). Slow-channel CMS (OMIM 601462) secondary to gain-of-function variants in the CHRND gene is inherited as a dominant condition (Shen et al. J Clin Invest 118:1867-1876, 2008; Müller et al. Brain 129:2784-2793, 2006). Null and low expressor CHRND variants in the homozygous or compound heterozygous state lead to CMS with end-plate AChR deficiency (Engel and Sine 2005). Lethal multiple pterygium syndrome is inherited as an autosomal recessive condition (Michalk et al. Am J Hum Genet 82:464-476, 2008).

The delta subunit if the acetylcholine receptor is encoded by exons 1 – 12 of the CHRND gene located on chr 2q37.1.

Sensitivity for CMS testing is at least 50% overall; 30% for CHRNE, 10% for RAPSN, and 7.5% for COLQ (GeneReviews, Abicht and Lochmüller, 2006). CHRND is a rare cause of CMS.

This test provides full coverage of all coding exons of the CHRND 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).