A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation

Abstract Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2 -CDG, the complete clinical picture of other types is not known. RFT1 -CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.