Intellectual disability - microarray and sequencing
Gene: NUP188 Amber List (moderate evidence)Green List (high evidence)
Comment on list classification: At least six unrelated families exhibiting a strikingly similar phenotype due to biallelic truncating variants in the NUP188 gene. Only 1/8 individuals survived beyond the first year of life and exhibited severe ID.
It is anticipated that other surviving patients would likely present the same phenotype; however, for now NUP188 will be rated Amber on the ID panel, awaiting further publications to corroborate the relevance of this manifestation.Created: 29 Sep 2020, 10:09 a.m. | Last Modified: 29 Sep 2020, 10:09 a.m.
Panel Version: 3.356
Associated with Sandestig-Stefanova syndrome in OMIM, but not yet in G2P.
- PMID: 32021605 (2020) - Two unrelated patients with different homozygous nonsense variants of NUP188, c.287dupA, p.Tyr96* and c.337C>T, p.Gln113*, respectively. Authors note strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, ventricular septal defect, and brain MRI anomalies (ventriculomegaly, loss of periventricular white matter, thin corpus callosum, and delayed myelination). Both ultimately died as a result of central respiratory failure at the age of 67 and 140 days, respectively.
- PMID: 32275884 (2020) - Six individuals from four unrelated families with bi-allelic truncating variants in NUP188 and similar phenotypes characterised by prenatal-onset ventriculomegaly or suspected brain malformation (4/6), congenital cataracts (4/6), congenital heart defects (5/5), hypotonia (5/6), brain MRI abnormalities (6/6) including ventriculomegaly loss of white-matter, hypoplastic corpus callosum, and delayed myelination. Progressive microcephaly consistent with a neurodegenerative process was noted in at least 3 cases. All six patients died of respiratory failure or respiratory-related illness: five within the first seven months of life; and the sixth at 2 years and 7 months, who also has severe ID and was non-ambulatory.Created: 29 Sep 2020, 9:54 a.m. | Last Modified: 29 Sep 2020, 9:54 a.m.
Panel Version: 3.355
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Sandestig-Stefanova syndrome, 618804
Publications
Green List (high evidence)
A total of 9 individuals reported with bi-allelic LoF variants and a consistent neurodevelopmental phenotype.Created: 13 Apr 2020, 12:19 a.m. | Last Modified: 13 Apr 2020, 12:19 a.m.
Panel Version: 3.24
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
The gene was present in the current panel with red rating, though with no reviews.
In Pubmed there are no publications concerning a link with ID. One publication (PMID: 21282601) reports on a 9q34.11 148 kb duplication spanning NUP188 as well as few other genes found in an individual with d-TGA (dextro-transposition of great arteries). Eventual other phenotypes are not commented on. A further publication (PMID: 28611029) reports on an individual heterozygous for a splice-site SNV but only cardiovascular phenotype is commented on again (mitral valve prolapse - variant : NM_015354.2:c.4737+1G>T).
There are no publications when searching for the alternative gene symbol (KIAA1069), either.
There is no associated phenotype in OMIM or G2P.
The gene is not included in the SysID and SFARI databases.
The denovo-db lists 4 non-synonymous de novo variants in individuals with autism or mixed phenotype.
[ http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=NUP188 ]
In Decipher, all CNVs encompassing NUP188 span also other proximal genes. There are no relevant SNVs.
The gene is part of the ID panel of VCGS (TGW024_genelist_V3 - Oct2018) which was also listed as source in the current panel.
Overall, red rating (or removal from the current panel) seems appropriate.Created: 24 Sep 2019, 4:40 p.m. | Last Modified: 24 Sep 2019, 4:40 p.m.
Panel Version: 2.1046
Phenotypes for gene: NUP188 were changed from to Sandestig-Stefanova syndrome, 618804
Publications for gene: NUP188 were set to
Mode of inheritance for gene: NUP188 was changed from to BIALLELIC, autosomal or pseudoautosomal
Gene: nup188 has been classified as Amber List (Moderate Evidence).
gene: NUP188 was added gene: NUP188 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: NUP188 was set to
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.