The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

Abstract

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Koolen-de Vries Syndrome: Clinical Report of an Adult and Literature Review

“…Among patients aged ≤ 18 years, attention deficit/hyperactivity disorder (ADHD or autistic trait) are reported [Koolen et al, 2016]. A friendly/amiable attitude was described in the majority of adult (8/10) and pediatric patients [Koolen et al, 2016]. Regarding dysmorphic features, all adult patients with KdS showed a long face.…”

“…In particular, 7 adult patients (aged >18 years, range 20-50 years) are included in the series reported by Koolen et al [2016] and 2 young adults (23-and 31-years-old) are described in the cohort reported by Zollino et al [2015]. Clinical and molecular data of these patients are summarized in table 1 .…”

“…Neuropsychological disorders were frequently observed in adulthood ranging from anxiety (5/10), stereotypic/behavioral problems (5/10), to poor eye contact (2/10); psychosis was recognized in 1 patient ( table 1 ). Among patients aged ≤ 18 years, attention deficit/hyperactivity disorder (ADHD or autistic trait) are reported [Koolen et al, 2016]. A friendly/amiable attitude was described in the majority of adult (8/10) and pediatric patients [Koolen et al, 2016].…”

“…troencephalography anomalies [Terrone et al, 2012, Koolen et al, 2016. Congenital cardiac defects (pulmonary stenosis 27%, septal defects 18%, bicuspid aortic valve 18%, patent ductus arteriosus or foramen ovale), acquired aortic dilatation, and urologic anomalies (82%, including cryptorchidism, hypospadias, vesicoureteral reflux) are commonly found.…”

“…Congenital cardiac defects (pulmonary stenosis 27%, septal defects 18%, bicuspid aortic valve 18%, patent ductus arteriosus or foramen ovale), acquired aortic dilatation, and urologic anomalies (82%, including cryptorchidism, hypospadias, vesicoureteral reflux) are commonly found. Most of the patients (58-73%) show joint hypermobility (JHM) during childhood, sometimes leading to hip dislocations (congenital or acquired) or positional deformities of the feet [Tan et al, 2009, Koolen et al, 2016. Additional features may include short stature according to genetic target, hearing loss (conductive, sensorineural or mixed, 26%), ectodermal abnormalities, hypermetropia, and other ocular defects [Zollino et al, 2015, Koolen et al, 2016].…”