A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly.
Osteogenesis imperfecta (OI) is a genetic disorder characterised by low bone mineral density resulting in fractures. 85-90% of patients with OI carry a variant in the type 1 collagen genes, COL1A1 and COL1A2, which follows an autosomal dominant pattern of inheritance. However, within the last two decades, there have been growing number of variants identified in genes that follow an autosomal recessive pattern of inheritance. Our proband is a child born in Mexico with multiple fractures of ribs, minimal calvarial mineralisation, platyspondyly, marked compression and deformed long bones. He also presented with significant hydranencephaly, requiring ventilatory support from birth, and died at 8days of age. A homozygous c.338_357delins22 variant in exon 2 of SERPINH1 was identified. This gene encodes heat shock protein 47, a collagen-specific chaperone which binds to the procollagen triple helix and is responsible for collagen stabilisation in the endoplasmic reticulum. There is minimal literature on the mechanism of action for variants in SERPINH1 resulting in osteogenesis imperfecta. Here we discuss this rare, previously unreported variant, and expand on the phenotypic presentation of this novel variant resulting in a severe, lethal phenotype of OI in association with hydranencephaly.
Medical School, University of Sheffield, UK.
Charlotte
C
Marshall
Genetics Department, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico; Neonatology Department, Hospital de la Mujer, Aguascalientes, Mexico.
Jaime
J
Lopez
Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
Laura
L
Crookes
Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
Rebecca C
RC
Pollitt
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK; Highly Specialised Severe, Complex & Atypical OI Service, Sheffield Children's NHS Foundation Trust, UK. Electronic address: meena.balasubramanian@nhs.net.
Meena
M
Balasubramanian
D000293:Adolescent; D001483:Base Sequence; D005091:Exons; D005260:Female; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006832:Hydranencephaly / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion
D050958:HSP47 Heat-Shock Proteins; C494660:SERPINH1 protein, human
Autosomal recessive; Hydranencephaly; Lethal presentation; Osteogenesis imperfecta