Sedaghatian-type spondylometaphyseal dysplasia: Whole exome sequencing in neonatal dry blood spots enabled identification of a novel variant in GPX4

Accumulation of lipid peroxides causes membrane damage and cell death. Glutathione peroxidase 4 (GPX4) acts as a hydroperoxidase which prevents accumulation of toxic oxidized lipids and blocks ferroptosis, an iron-dependent, non-apoptotic mode of cell death. GPX4 deficiency causes Sedaghatian-type spondylo-metaphyseal dysplasia (SSMD), a lethal autosomal recessive disorder, featuring skeletal dysplasia, cardiac arrhythmia and brain anomalies with only three pathogenic GPX4 variants reported in two SSMD patients. Our objective was to identify the underlying genetic cause of neonatal death of two siblings presenting with hypotonia, cardiorespiratory failure and SSMD. Whole exome sequencing (WES) was performed in DNA samples from two siblings and their parents. Since “critical samples” were not available from the patients, DNA was extracted from dry blood spots (DBS) retrieved from the Israeli newborn-screening center. Sanger sequencing and segregation analysis followed the WES. Homozygous novel GPX4 variant, c.153_160del; p.His52fs*1 causing premature truncation of GPX4 was detected in both siblings; their parents were heterozygotes. Segregation analysis confirmed autosomal recessive inheritance. This report underscores the importance of DBS WES in identifying the genes and mutations causing devastating rare diseases. Obtaining critical samples from a dying patient is crucial for enabling genetic diagnosis.