Clinical spectrum of Kabuki‐like syndrome caused by HNRNPK haploinsufficiency

• Published in: Clinical genetics Vol. 93; no. 2; pp. 401 - 407
• Main Authors: Dentici, Maria Lisa, Barresi, Sabina, Niceta, Marcello, Pantaleoni, Francesca, Pizzi, Simone, Dallapiccola, Bruno, Tartaglia, Marco, Digilio, Maria Cristina
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2018
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - physiopathology; Child; Congenital defects; Cranial sutures; Craniosynostosis; Differential diagnosis; exome; Exome - genetics; Face - abnormalities; Face - physiopathology; Female; Growth rate; Haploinsufficiency; Haploinsufficiency - genetics; Hematologic Diseases - genetics; Hematologic Diseases - physiopathology; Heterogeneous-Nuclear Ribonucleoprotein K - genetics; HNRNPK; Humans; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Kabuki syndrome; Mutation; nodular heterotopia; Phenotype; Polydactyly; Vestibular Diseases - genetics; Vestibular Diseases - physiopathology; Whole Exome Sequencing; Kabuki syndrome; craniosynostosis; HNRNPK; exome; nodular heterotopia; polydactyly
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.13029

Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11‐year‐old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole‐exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.