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

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

  • Am J Hum Genet. 2020 May 7;106(5):623-631. doi: 10.1016/j.ajhg.2020.03.009.
Alison M Muir 1,  Jennifer L Cohen 2,  Sarah E Sheppard 2,  Pavithran Guttipatti 3,  Tsz Y Lo 3,  Natalie Weed 1,  Dan Doherty 4,  Danielle DeMarzo 5,  Christina R Fagerberg 6,  Lars Kjærsgaard 7,  Martin J Larsen 6,  Patrick Rump 8,  Katharina Löhner 8,  Yoel Hirsch 9,  David A Zeevi 9,  Elaine H Zackai 2,  Elizabeth Bhoj 2,  Yuanquan Song 10,  Heather C Mefford 11
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 2 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 3 Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
  • 5 Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73104, USA.
  • 6 Department of Clinical Genetics, Odense University Hospital, Denmark.
  • 7 Hans Christian Andersen Children's Hospital, Odense University Hospital, Denmark.
  • 8 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 9 The Committee for Prevention of Jewish Genetic Diseases, Dor Yeshorim, Jerusalem, Israel.
  • 10 Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 11 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID: 32275884 DOI: 10.1016/j.ajhg.2020.03.009
Abstract

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.

Keywords

Ashkenazi Jewish; NUP188; autosomal recessive; congenital cataracts; congenital heart defects; dendritic arborization; microcephaly; negative geotaxis; nuclear pore complex; nucleoporin.

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