Intellectual disability - microarray and sequencing
Gene: NKAPComment on list classification: NKAP reviewed by Konstantinos Varvagiannis following publication by Fiordaliso et al. (PMID:31587868) who identified 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) was seen in 4 families and although origin was not provided for all families this variant was seen in brothers with parents from Slovakia and an individual with parents from Japan.
NKAP is not currently in OMIM or Gene2Phenotype.
Rating NKAP as Green as consistent phenotype observed, >3 unrelated individuals and some functional work in Zebrafish.Created: 24 Oct 2019, 5:09 p.m. | Last Modified: 24 Oct 2019, 5:09 p.m.
Panel Version: 2.1091
Fiordaliso et al. (2019 - DOI: 10.1016/j.ajhg.2019.09.009) report on 10 males with missense mutations in NKAP (on Xq24)
Hypotonia, DD/ID (10/10 - relevant to the current panel based on the descriptions in the supplement), tall stature with Marfanoid habitus were observed in all. Other features included variable cardiac manifestations (mitral valve regurgitation/prolapse, ASD, VSD, PDA, aortic root dilatation), genitourinary anomalies, obesity or behavioral anomalies. Some facial features appeared to be more common/shared.
NKAP encodes NF-κB-activating protein, an ubiquitously expressed nuclear speckle protein reported to have - among others - an important role in transcriptional regulation and mRNA splicing/exon ligation [several studies cited].
All (5 different) variants reported were missense SNVs, localizing in the last 2 exons (ex8,9) encoding the C-terminal part of the protein (aa 273-415) harboring the HDAC3 transcriptional repression domain. One variant was recurrent, observed in 4 families (NM_024528:c.988G>A / p.Arg333Gln).
gnomAD does not list any missense variants in the region between Pro296 and Glu394 (ex7-9), nor any truncating NKAP variant overall.
In 4 individuals the variant had occurred as a de novo event. Further occurrence in 2 affected sibs as an apparently de novo event suggested maternal germline mosaicism. 3 affected males had inherited the variant from their mother (segregation confirmed in one family of 4 affected males and 2 carrier females from 3 generations). In 1 case inheritance was unknown. Carrier mothers were either unaffected or much less severely affected (the gene is subject to X-inactivation).
NKAP mRNA and protein levels in LCLs from affected individuals (1-2 variants tested respectively) were similar to controls.
Immunofluorescence in LCLs showed similar NKAP localization for mt / wt demonstrating a nuclear speckled pattern. Localization and levels of HDAC3 were also similar when comparing LCLs from controls / and an affected individual.
RNA-seq in LCLs from individuals with Arg333Gln and Arg361Gln revealed a consistent transcriptome profile (different from LCLs from controls) with upregulation of >400 genes and downregulation of >700 ones. Downregulation appeared to affect - in particular - long genes with higher number of exons.
In mice, Nkap lies on the X-chromosome and hemizygous Nkap-null mutants show embryonic lethality (ref. provided in article).
Zebrafish homozygous for a frameshift variant in the penultimate exon (most likely escaping NMD as also testing suggested) have severe developmental defects including spine deformities with none surviving beyond 4 dpf. Homozygosity for a nkap variant affecting the start codon in zebrafish, resulted to similar developmental defects (ref. for the latter, provided in article).
The C-terminal domain is suggested to be critical for development, based on the clustering of patient variants, the complete absence of missense variants in this domain in gnomAD as well as the zebrafish model.
(Individuals from previous studies eg. the DDD study or from Hackmann et al. have been included in this report and were not further considered)
-------
NKAP is not associated with any phenotype in OMIM/G2P/SysID.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
-------
As a result, NKAP can be considered for inclusion in the ID panel probably as green (>3 patients/families/variants, consistent phenotype and relevant severity, segregation studies, some supporting evidence from transcriptional dysregulation and development in zebrafish) or amber.Created: 6 Oct 2019, 7:17 p.m. | Last Modified: 6 Oct 2019, 7:17 p.m.
Panel Version: 2.1062
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Global developmental delay; Intellectual disability; Tall stature; Scoliosis; Pectus excavatum; Pectus carinatum; Arachnodactyly; Camptodactyly; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of the face; Obesity
Publications
Comment on publications: Candidate gene suggested by Grozeva et al, (2015) PMID: 26350204Created: 28 Feb 2018, 4:55 p.m.
Comment on publications: added recent paper Hackmann K et al., 2016 (PMID: 26358559). A recent analysis of s small cohort with a clinical diagnosis of Lujan-Fryns syndrome (LFS) comprised of X-linked intellectual disability (XLID) with marfanoid habitus. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each.Created: 28 Feb 2018, 4:54 p.m.
This is a candidate intellectual disability gene from Grozeva et al, (2015) PMID: 26350204, however no evidence to date has been found to support the association between variants of this gene and an observed intellectual disability phenotype.Created: 28 Feb 2018, 4:47 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: NKAP were changed from Global developmental delay; Intellectual disability to Global developmental delay; Intellectual disability; Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type #301039
Phenotypes for gene: NKAP were changed from to Global developmental delay; Intellectual disability
Gene: nkap has been classified as Green List (High Evidence).
Tag missense tag was added to gene: NKAP.
Publications for gene: NKAP were set to 26358559; 26350204
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene NKAP was set to ['26358559', '26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
NKAP was created by ellenmcdonagh
NKAP was added to Intellectual disabilitypanel. Sources: Expert Review Red