Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies

Miriam S Reuter; Michael Zech; Maja Hempel; Janine Altmüller; Tracy Heung; Laura Pölsler; René Santer; Holger Thiele; Brett Trost; Christian Kubisch; Stephen W Scherer; Sabine Rudnik-Schöneborn; Anne S Bassett; Davor Lessel

doi:10.1038/s41431-022-01077-y

Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies

Eur J Hum Genet. 2022 May;30(5):611-618. doi: 10.1038/s41431-022-01077-y. Epub 2022 Mar 18.

Authors

Miriam S Reuter^#^{1

2

3}, Michael Zech^#^{4

5}, Maja Hempel^#⁶, Janine Altmüller⁷, Tracy Heung⁸, Laura Pölsler⁹, René Santer¹⁰, Holger Thiele⁷, Brett Trost^{11

12}, Christian Kubisch⁶, Stephen W Scherer^{11

12

13

14}, Sabine Rudnik-Schöneborn⁹, Anne S Bassett^{8

15

16

17}, Davor Lessel⁶

Affiliations

¹ CGEn, The Hospital for Sick Children, Toronto, ON, Canada. miriam.reuter@sickkids.ca.
² The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada. miriam.reuter@sickkids.ca.
³ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. miriam.reuter@sickkids.ca.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
⁵ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Cologne Center for Genomics, University of Cologne and University Hospital Cologne, Cologne, Germany.
⁸ Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁹ Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
¹⁰ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
¹² Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁴ McLaughlin Centre, University of Toronto, Toronto, ON, Canada.
¹⁵ Division of Cardiology, Toronto Congenital Cardiac Centre for Adults at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network, Toronto, ON, Canada.
¹⁶ The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Psychiatry, and Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
¹⁷ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

^# Contributed equally.

Abstract

PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.

MeSH terms

Abnormalities, Multiple* / genetics
Dwarfism*
Humans
Intellectual Disability* / genetics
Muscle Hypotonia
Neurodevelopmental Disorders* / genetics
Phenotype
RNA, Messenger / metabolism

Substances

RNA, Messenger

Grants and funding

CIHR/Canada