calpain and Developmental-Disabilities

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

Mutations that activate the protease calpain-5 (

Topics: Alleles; Amino Acid Sequence; Calpain; Child, Preschool; Developmental Disabilities; Electroencephalography; Exome Sequencing; Genetic Association Studies; Genotype; Hearing Loss; Humans; Male; Models, Molecular; Mutation; Pedigree; Phenotype; Protein Conformation; Vitreoretinopathy, Proliferative

Uniparental disomy (UPD) is an unusual situation wherein two homologous chromosomes are inherited from the same parent. UPDs can cause clinical abnormalities owing to the aberrant dosage of genes regulated by epigenetic imprinting or homozygosity of variants for recessive phenotypes. The aim of this study was to identify the genetic cause of the obesity and developmental delay phenotype in a 3-year-old Chinese boy.. Chromosomal microarray analysis (CMA) was used for detecting potential copy number variations (CNVs) and homozygous segments. Whole-exome sequencing (WES) identified sequence variants. Sanger sequencing further confirmed the variants in GPBAR1 and CAPN10 both in the patient and the parents.. No clinically significant CNVs were identified by CMA but a complete UPD of chromosome 2 (UPD2) was revealed in the patient. WES identified a total of 13 rare homozygous single-nucleotide variants (SNVs) on chromosome 2. Among the 13 SNVs, a nonsense variation in GPBAR1 (c.753T>G; p.Y251*) and a missense variation in CAPN10 (c.413C>T; p.S138F) were evaluated as candidate disease-causing variants based on their functional impacts to their respective protein and the biological relevance of the genes to the clinical presentation of our patient. Both GPBAR1 and CAPN10 variants were detected in the patient's mother in a heterozygous state, indicating that the patient had maternal UPD2. No other clinically relevant variants were identified.. Homozygosity of rare recessive variations caused by UPD2 likely contributed to the phenotypes of our patient. Based on emerging evidence, the nonsense variation in GPBAR1 and the missense variation in CAPN10 are considered as causally related to our patient's phenotype, that is, obesity and delayed development, respectively. The present study further supports the role of GPBAR1 in obesity and the role of calpain-10 in neurological function.

Topics: Abnormalities, Multiple; Asian People; Calpain; Child, Preschool; China; Chromosomes, Human, Pair 2; Developmental Disabilities; DNA Copy Number Variations; Genotype; Humans; Male; Mutation; Pediatric Obesity; Protein Array Analysis; Receptors, G-Protein-Coupled; Uniparental Disomy