Arthrogryposis multiplex congenita, distal, type 1B (DA1B)

 Clinical summary

Distal arthrogryposis type 1 (DA1) is characterized by multiple contractures of hands and feets (camptodactyly and clubfoot), no visceral organ involvement and normal intelligence. Large multigenerational families have been reported. DA1 type B (DA1B) is caused by mutation in the in the MYBPC1 gene (heterozygous mutations in this gene also cause DA type 2). The other form of DA1 (DA1A) is caused by mutation in the TPM2 gene, which also associates to DA2B and to nemaline myopathy 4.

Detailed clinical description

Congenital talipes equinovarus (clubfoot) and congenital vertical talus can be observed. Lower limb contractures tend to be bilateral, but can also affect one side only. Hand contractures manifesting as either camptodactyly and ulnar deviation of the fingers or extension contracture of the fourth digit can be seen, but some patients may lack hand involvement. Incomplete penetrance and variable expressivity have been reported. There is basically no difference with DA1A and the distinction is purely based on the genetic cause.

Molecular genetics

DA1B is caused by a heterozygous, likely gain-of-function mutation in the MYBPC1 (autosomal dominant inheritance). The heterozygous mutations causing the autosomal dominant form are c.706T>C (p.Trp236Arg) and c.2566T>C (p.Tyr856His). However, a homozygous mutation causing a mild, autosomal recessive form of arthrogryposis – c.556G>A (p.E286K / p.Glu286Lys) – has also been reported. Another homozygous mutation – c.952C>T (p.Arg318Ter) – reportedly causes lethal congenital contracture syndrome 4 (LCCS4). Two novel MYBPC1 mutations – c.1075G>A (p.E359K / p.Glu359Lys) and c.956C>T (p.P319L / p.Pro319Leu) – have been found to be responsible for DA2 in Chinese families (one of these mutations was introduced by germline mosaicism).

Genetic testing strategy

Targeted mutation analysis can be done to detect arthrogryposis and LCCS known mutations such as c.706T>C (p.Trp236Arg), c.2566T>C (p.Tyr856His), c.556G>A (p.Glu286Lys), c.952C>T (p.Arg318Ter), c.1075G>A (p.Glu359Lys) and c.956C>T (p.Pro319Leu). However, since arthrogryposes are genetically and clinically heterogeneous, full MYBPC1 gene sequencing (EXOME GENE) or panel testing (EXOME PANEL) is recommended.

Panel testing recommended at Breda Genetics for this condition: