Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism

TNNI2 at 11p15.5 encodes troponin I2, fast skeletal type, which is a member of the troponin I gene family and a component of the troponin complex. Distal arthrogryposis (DA) is characterized by congenital limb contractures without primary neurological or muscular effects. DA is inherited in an autosomal dominant fashion and is clinically and genetically heterogeneous. Exome sequencing identified a causative variant in TNNI2 [NM_003282.4:c.532T > C p.(Phe178Leu)] in a Japanese girl with typical DA2b. Interestingly, the familial study using Sanger sequencing suggested a mosaic variant in her healthy father. Subsequent targeted amplicon-based deep sequencing detected the TNNI2 variant with variant allele frequencies of 9.4-17.7% in genomic DNA derived from peripheral blood leukocytes, saliva, hair, and nails in the father. We confirmed a disease-causing variant in TNNI2 in the proband inherited from her asymptomatic father with its somatic variant. Our case demonstrates that careful clinical and genetic evaluation is required in DA.

Automated summary

TNNI2 at 11p15.5 is responsible for encoding troponin I2, a component of the troponin complex. Distal arthrogryposis (DA) is a genetically heterogeneous disorder characterized by congenital limb contractures. Exome sequencing identified a disease-causing variant in TNNI2 in a Japanese girl with typical DA2b, and a mosaic variant in her asymptomatic father was detected through subsequent targeted sequencing. Our case highlights the importance of careful clinical and genetic evaluation in DA.