Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

Paul Kruszka,Ariel F Martinez,Sung‐Kook Hong,James C Mullikin,Elaine H Zackai,Roger E Stevenson,Leon Mutesa,Annette Uwineza,Robert S Adelstein,Rebecca Ganetzky,Xuefei Ma,Yu Abe,Maximilian Muenke,Brian Chung

doi:10.1002/mgg3.153

Abstract

Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

Highlights

Limb body wall complex (LBWC) is a usually fatal multiple congenital anomaly condition with craniofacial, limb, and ventral wall defects
Multiple prediction models were used to evaluate the potential pathogenicity of the variant, including a Combined Annotation-Dependent Depletion (CADD) score of 39.0, a Grantham score of 29, a genomic evolutionary rate profiling (GERP) score of 5.6, and a PolyPhen-2 (Polymorphism Phenotyping v2) prediction of “probably damaging.”
This mutation was not found in multiple databases including 1000 Genomes, the Exome Aggregation Consortium (ExAC), and the NHLBI Exome Sequencing Project (ESP)

Summary

Introduction

Limb body wall complex (LBWC) is a usually fatal multiple congenital anomaly condition with craniofacial, limb, and ventral wall defects. Many of the anomalies of LBWC are found in amniotic band sequence (ABS) including craniofacial malformations, a 2015 The Authors. We can confirm a genetic etiology, IQ Motif Containing K (IQCK), for a patient who fits some characteristics of ABS and LBWC or may represent a new syndrome.

Results

Conclusion