NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?

Abstract

There is no clearly established association between the gene <i>NUP188</i> and human pathology. Only a few reports of patients with different clinical presentation and different heterozygous or compound heterozygous missense or splice region variants have been identified in several sequencing projects; however, a causative association between the clinical features and the identified variants has not been established. For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of <i>NUP188</i>, p.Tyr96* and p.Gln113*, respectively. Although having different supposedly truncating mutations, the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization. Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix. They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure. Our findings strongly suggest a correlation between the homozygous nonsense gene variants of <i>NUP188</i> and a severe phenotype of a new developmental syndrome with poor prognosis resulting from nucleoporin 188 homolog protein insufficiency.

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities

“…Recently, homozygous truncating variants in NUP188 were reported in two additional individuals who had a similar severe phenotype and who also died of respiratory failure within the first year of life. 31 Evaluation of NUP188 should be considered in infants with neurologic deficits, congenital cataracts, congenital heart defects, and unexplained respiratory failure, and particularly heightened attention should be given to infants of Ashkenazi Jewish descent.…”

A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities

“…In addition to these, the facial shapes were also found to be similar. The homozygous truncating NUP188 mutations observed in both children underlay all these abnormalities suggesting the presence of "nucleoporin 188 deficiency syndrome" [Sandestig et al, 2020].…”

“…Sandestig-Stefanova syndrome is a newly defined syndrome and has been described in only 2 studies in the literature to date [Muir et al, 2020;Sandestig et al, 2020]. We describe a novel variant in the NUP188 gene in a male patient, which has not been reported in genetic databases and in the literature before.…”

“…NPCs are water channels built by a complex network of proteins known as nucleoporins that control all entry and exit between the nucleus and cytoplasm [Jühlen and Fahrenkrog, 2018]. Sandestig et al [2020] performed trio-exome sequencing on 2 unrelated girls with similar congenital anomalies and their parents. Both girls died a few months after birth due to central respiratory failure.…”

“…reported for the first time that biallelic loss-of-function mutations in the NUP188 gene caused a new autosomal recessive developmental syndrome named Sandestig-Stefanova syndrome (SAND-STEF; OMIM #618804). This syndrome is characterized by microcephaly before and after birth, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis [Sandestig et al, 2020]. Although pathogenic nucleo-porin (NUP) 188 variants cause multisystem disorders, affected individuals usually present with central nervous system (CNS) findings.…”