SERPINA11 related novel serpinopathy - A perinatal lethal disorder.

SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in SERPINA11, and provide functional evidence to support its candidature as a Mendelian disorder. The SERPINA11 variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced SERPINA11 transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.

Muscle spasms as presenting feature of Nivelon-Nivelon-Mabile syndrome.

Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.