calpain and Growth-Disorders

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium-specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue-specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi-allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson-Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base-pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out-of-frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss-of-function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson-Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

Topics: Abnormalities, Multiple; Alleles; Anus, Imperforate; Base Pairing; Calpain; Codon, Nonsense; Consanguinity; Developmental Disabilities; Ectodermal Dysplasia; Eye Abnormalities; Genetic Association Studies; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; INDEL Mutation; Intellectual Disability; Introns; Male; Microphthalmos; Muscle Hypotonia; Nose; Pancreatic Diseases; Pedigree; RNA Splice Sites; Sequence Deletion; Steatorrhea