Hackmann-Di Donato Syndrome

Mendelian MONDO:0026733 Pathograph 31 Show in embeddings browser X-linked syndromic intellectual disability

Hackmann-Di Donato syndrome (MRXSHD) is an X-linked syndromic intellectual developmental disorder caused by hemizygous missense variants in NKAP, which encodes NF-kappa-B activating protein, a ubiquitously expressed nucleoplasmic transcriptional regulator that acts in an HDAC3-containing corepressor complex and associates with the post-catalytic spliceosome. The reported variants cluster in the C-terminal region that mediates those interactions. Affected males show a highly conserved picture of developmental delay and intellectual disability, hypotonia, a Marfanoid habitus with tall stature, arachnodactyly and joint hypermobility, scoliosis, joint contractures, behavioural abnormalities, a recognisable facial gestalt (long face, high palate, large protruding ears, epicanthus, short philtrum) and, in a majority, congenital cardiovascular anomalies. Fewer than twenty affected individuals have been reported, including two fetuses ascertained through severe congenital heart defects. Patient-derived cells carry a transcriptome signature of downregulated long, exon-rich genes, which is the mechanistic basis currently proposed.

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1
Inheritance
9
Pathophys.
25
Phenotypes
2
Gaps
31
Pathograph
1
Genes
2
Variants
3
Medical Actions
3
Models
12
References
1
Deep Research
👪

Inheritance

1
X-linked recessive HP:0001419
Hemizygous males are affected. Familial transmission from unaffected or much less severely affected heterozygous mothers has been documented in several families; the remaining cases in the original cohort were apparently de novo, and one pair of affected brothers born to an unaffected mother indicates maternal germline mosaicism, so an apparently de novo case still carries a recurrence risk. In a mouse model, females heterozygous for a deleterious Nkap allele show extreme skewing of X-chromosome inactivation against the mutant-bearing X, which offers a mechanism for the unaffected carrier state; the same phenomenon has unmasked haemophilia A in a human carrier of a disruptive NKAP variant.
X-linked recessive inheritance
Show evidence (3 references)
PMID:42481913 SUPPORT Human Clinical
"Among these cases, evidence of familial transmission has been documented in five individuals from three unrelated families."
Documents inherited (maternal) transmission consistent with X-linked recessive inheritance.
PMID:41828556 SUPPORT Model Organism
"XCI pattern analysis using methylation-sensitive restriction enzymes demonstrated that mutant NKAP/HA females exhibited significant XCI skewing of the X chromosome bearing the mutant NKAP copy."
Shows in mice that the mutant-NKAP X is preferentially inactivated in heterozygous females, explaining why carrier females are unaffected.
PMID:41828556 SUPPORT BACKGROUND Human Clinical
"We have previously reported that a disruptive NKAP mutation resulted in extremely skewed X chromosome inactivation (XCI), leading to phenotypic manifestation of hemophilia A (HA) in a HA carrier."
The human observation of NKAP-driven X-inactivation skewing in a heterozygous female, restated in this paper's introduction.
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Discussions and Knowledge Gaps

2
NKAP depletion causes R-loop accumulation, DNA damage and replication stress in cell lines through loss of the NKAP-HDAC3 complex. Do the hemizygous C-terminal missense alleles, which retain protein but lose HDAC3 binding, produce the same R-loop phenotype in patient cells?
KNOWLEDGE GAP nkap_missense_r_loop_genome_instability
Attached to
pathophysiology#Loss of NKAP-HDAC3 Corepressor Complex Function pathophysiology#Reduced Cellular Proliferation and Senescence
The patient transcriptome signature (downregulated long, exon-rich genes) is also what transcription-coupled R-loop stress would be expected to produce, and mutant embryonic fibroblasts proliferate poorly and senesce. Resolving this would decide whether the disorder is one of transcriptional corepression, of splicing, or of genome maintenance.
Show evidence (1 reference)
PMID:37322264 SUPPORT INDIRECT In Vitro
"In addition, NKAP prevents R-loop formation by maintaining RNA polymerase II pausing."
The depletion result that raises the question; it was obtained without patient alleles.
Both animal models carry alleles that truncate or disrupt Nkap (a C-terminal truncation in zebrafish; an N-terminal in-frame deletion in the mouse), whereas the human disease is caused by C-terminal missense variants that leave protein level unchanged. Do the model phenotypes reflect loss of the C-terminal interactions, or a null state the human alleles do not reach?
HUMAN MODEL MISMATCH nkap_animal_alleles_vs_human_missense
Attached to
animal_models#nkap C-terminal truncation zebrafish animal_models#Nkap mutant mouse (hemizygous males)
Complete NKAP loss is lethal in mouse haematopoiesis and T cell development, which affected humans do not show, so the human alleles are at most hypomorphic for those functions. A knock-in of a patient allele would separate the two.
Show evidence (1 reference)
PMID:20610818 SUPPORT INDIRECT Model Organism
"These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival."
Complete loss is lethal to haematopoiesis in mice, which affected humans do not show, so the human alleles cannot be nulls for this function.
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Pathophysiology

9
NKAP C-terminal Missense Variant
Hemizygous missense variants in NKAP, clustered in exons 8 and 9 encoding the conserved C-terminal (DUF926) region through which NKAP binds HDAC3 and post-catalytic spliceosomal proteins. Reported alleles include p.Arg330Cys, p.Arg330His, p.Arg333Gln, p.Ile337Thr and p.Arg361Gln. One proband carried an exon 4 variant (p.Arg204Ser) of uncertain significance, which, if confirmed, would widen the mutational spectrum beyond the C-terminal cluster.
NKAP hgnc:29873 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NKAP (hgnc:29873). hgnc:29873 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS
Hemizygous missense alleles in males. The functional category is not established: transfected p.Arg330Cys lowers NKAP transcript but not protein and disturbs HDAC3 binding and intranuclear distribution, consistent with a partial loss of corepressor function rather than a null.
transcription corepressor activity GO:0003714 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology. histone deacetylase binding GO:0042826 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone deacetylase binding (GO:0042826). GO:0042826 is a molecular function from the Gene Ontology.
Animal models
nkap C-terminal truncation zebrafish Zebrafish perturbs Removes the C-terminal region in which the human missense variants cluster and produces developmental defects; it perturbs the region rather than reproducing a missense lesion.
Downstream
Loss of NKAP-HDAC3 Corepressor Complex Function The recurrent p.Arg330Cys allele disturbs NKAP binding to HDAC3 and its intranuclear distribution.
Perturbed Spliceosomal Exon-Ligation Association The variant cluster lies in the region that contacts the post-catalytic spliceosome; a functional consequence for splicing is inferred, not yet shown.
Reduced Cellular Proliferation and Senescence Shown only for a mouse allele that is an in-frame 123 bp deletion in exon 1 (N-terminal RS domain), not a C-terminal missense change; whether the human alleles produce the same cellular defect is untested.
Show evidence (2 references)
PMID:31587868 SUPPORT Human Clinical
"These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins."
Establishes the C-terminal clustering of the causal missense variants and the interaction surfaces they fall on.
PMID:41917976 SUPPORT BACKGROUND Human Clinical
"All previously reported patients had mutations located in exons 8 and 9 of NKAP."
Localises the established variant cluster to exons 8 and 9.
Loss of NKAP-HDAC3 Corepressor Complex Function
NKAP is a transcriptional repressor that associates with histone deacetylase 3 and with the Notch corepressor complex, and it must bind HDAC3 to act in T cell maturation and haematopoietic stem cell survival. Mutant NKAP loses HDAC3 binding and mislocalises within the nucleus, so corepressor activity at NKAP target genes, including Notch targets, is expected to fall.
negative regulation of Notch signaling pathway GO:0045746 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of Notch signaling pathway (GO:0045746). GO:0045746 is a biological process from the Gene Ontology.
transcription corepressor activity GO:0003714 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology. histone deacetylase binding GO:0042826 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone deacetylase binding (GO:0042826). GO:0042826 is a molecular function from the Gene Ontology.
Experimental models
HEK293T cells expressing NKAP p.Arg330Cys CELL LINE Shows reduced HDAC3 binding and altered intranuclear distribution of the mutant protein.
Downstream
Dysregulated Cardiac Morphogenesis Gene Expression The authors attribute the cardiac gene dysregulation produced by p.Arg330Cys to the allele's altered intranuclear distribution and obstructed HDAC3 binding.
Transcriptional Dysregulation of Long Exon-rich Genes Loss of corepressor function is the proposed route to the patient transcriptome signature.
Show evidence (2 references)
PMID:19409814 SUPPORT INDIRECT In Vitro
"NKAP associated with the histone deacetylase HDAC3 and was shown to be part of a DNA-binding complex, as demonstrated by chromatin immunoprecipitation. NKAP also associated with the Notch corepressor complex."
Defines the HDAC3 and Notch-corepressor interactions of wild-type NKAP that the C-terminal variants disturb; the disease relevance is inferred.
PMID:38647244 SUPPORT In Vitro
"Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level."
Shows the recurrent allele does not abolish the protein, supporting a qualitative loss of complex function rather than absence.
Perturbed Spliceosomal Exon-Ligation Association
NKAP is a nuclear speckle protein that, with CACTIN and SDE2, stabilises the catalytic conformation of the human post-catalytic spliceosome during exon ligation. The disease variants fall in the region that mediates this association, so a splicing contribution to the transcriptome signature is plausible but has not been demonstrated in patient cells.
mRNA splicing, via spliceosome GO:0000398 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated mRNA splicing, via spliceosome (GO:0000398). GO:0000398 is a biological process from the Gene Ontology.
Downstream
Transcriptional Dysregulation of Long Exon-rich Genes A defect in exon ligation would be expected to bear hardest on long genes with many exons, which is the class the patient signature downregulates.
Show evidence (1 reference)
PMID:30705154 SUPPORT INDIRECT In Vitro
"CACTIN, SDE2, and NKAP-factors implicated in alternative splicing-further stabilize the catalytic conformation of the spliceosome during exon ligation."
Structural evidence for NKAP's role in exon ligation in the wild-type spliceosome; the effect of the disease alleles is inferred.
Transcriptional Dysregulation of Long Exon-rich Genes
Transcriptome analysis of cells from affected individuals shows a distinctive signature in which long genes with higher exon numbers are downregulated. This is the defining cellular phenotype of the disorder and the reason it is described as a disorder of transcriptional regulation.
regulation of DNA-templated transcription GO:0006355 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology.
Downstream
Impaired Neurodevelopment Perturbation of the NKAP C-terminal region produces developmental defects in humans and zebrafish; which dysregulated transcripts drive the neurodevelopmental phenotype is not known.
Abnormal Skeletal and Connective Tissue Development The Marfanoid skeletal picture is attributed to the same transcriptional defect; no connective-tissue target gene has been identified.
Show evidence (1 reference)
PMID:31587868 SUPPORT Human Clinical
"In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers."
Direct report of the transcriptome signature in affected individuals.
Dysregulated Cardiac Morphogenesis Gene Expression
NKAP p.Arg330Cys dysregulates transcription of cardiac morphogenesis genes including DHRS3, DNAH11 and JAG1, which the authors attribute to lost HDAC3 binding and mislocalisation of the mutant protein, offering a route to the congenital heart defects seen in a majority of affected males and in both reported fetuses. DHRS3 moved in the opposite direction in patient lymphoblastoid cells, so the direction of individual gene changes is not settled.
heart morphogenesis GO:0003007 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated heart morphogenesis (GO:0003007). GO:0003007 is a biological process from the Gene Ontology.
Downstream
Congenital heart defect Proposed explanation for the fetal and postnatal cardiac malformations.
Ventricular septal defect The authors' proposed route from p.Arg330Cys to the septal and outflow malformations seen in the fetuses.
Show evidence (1 reference)
PMID:38647244 SUPPORT In Vitro
"Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1."
Reports the cardiac developmental gene dysregulation produced by the patient allele.
Impaired Neurodevelopment
NKAP is highly expressed in neural progenitor cells and migrating neuroblasts of the mammalian subventricular zone and in mature neurons of several regions, and the syndrome is grouped with the nuclear speckleopathies, in which developmental disability is the shared feature. The neuroanatomical basis of the intellectual disability is largely unexamined; white matter lesions were found in one familial case.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
neurogenesis GO:0022008 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neurogenesis (GO:0022008). GO:0022008 is a biological process from the Gene Ontology.
Animal models
Nkap mutant mouse (hemizygous males) Mouse partially recapitulates Gait alteration is the only neurological readout and is interpreted as a hypotonia correlate.
Downstream
Global developmental delay
Intellectual disability
Hypotonia
Aggressive behavior
Abnormal cerebral white matter
Show evidence (2 references)
PMID:24583034 SUPPORT INDIRECT Model Organism
"NKAP is highly expressed in Mash1(+) transit amplifying cells and PSA-NCAM(+) migrating neuroblasts throughout the subventricular zone (SVZ) and the rostral migratory stream (RMS), as well as in the hippocampus."
Expression in neurogenic progenitors makes neurodevelopment a plausible site of action; it does not itself show a defect.
PMID:36929417 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development."
Places NKAP-related syndrome among the nuclear speckleopathies whose shared feature is developmental disability.
Abnormal Skeletal and Connective Tissue Development
Affected males have a Marfanoid habitus with tall stature, long limbs, arachnodactyly, joint hypermobility, pectus deformity, scoliosis and joint contractures. The connective-tissue mechanism is unknown; FBN1-independent Marfanoid phenotypes with intellectual disability are a recognised group that also includes Lujan-Fryns syndrome.
Downstream
Marfanoid habitus
Tall stature
Arachnodactyly
Joint hypermobility
Scoliosis
Pectus deformity
Joint contractures
Show evidence (1 reference)
PMID:41828556 SUPPORT BACKGROUND Human Clinical
"Males with missense NKAP mutations have been reported to present with marfanoid features and behavioral and musculoskeletal abnormalities."
Summarises the musculoskeletal and Marfanoid picture of affected males.
Reduced Cellular Proliferation and Senescence
Embryonic fibroblasts hemizygous for a deleterious Nkap allele show markedly reduced proliferation and increased senescence. In heterozygous females this confers a growth disadvantage on cells whose active X carries the mutant allele, producing the extreme X-inactivation skewing seen in carriers. Whether the human missense alleles reproduce this is untested; complete NKAP loss causes R-loop accumulation and genome instability in cell lines.
embryonic fibroblast CL:2000042 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves embryonic fibroblast (CL:2000042). CL:2000042 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. cellular senescence GO:0090398 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology.
Animal models
Nkap mutant mouse (hemizygous males) Mouse recapitulates Embryonic fibroblasts from this model are the source of the proliferation and senescence observation.
Downstream
Skewed X-Inactivation in Heterozygous Females Secondary selection against cells expressing the mutant allele.
Show evidence (2 references)
PMID:41828556 SUPPORT In Vitro
"Murine embryonic fibroblasts (MEFs) derived from a hemizygous mutant NKAP embryo exhibited markedly reduced proliferation rate and increased senescence compared to WT NKAP MEFs"
Direct measurement of the proliferation and senescence defect in mutant cells.
PMID:37322264 SUPPORT INDIRECT In Vitro
"Here, we show that NKAP (NF-κB activating protein) is essential for preventing R-loop accumulation and maintaining genome integrity through forming a protein complex with HDAC3."
NKAP depletion in cell lines causes R-loop-associated genome instability, a candidate basis for the proliferation defect; the study used depletion, not patient alleles.
Skewed X-Inactivation in Heterozygous Females
Heterozygous female mice preferentially inactivate the X bearing the mutant Nkap allele, and in a double-mutant model this silences a wild-type F8 allele in cis, reducing factor VIII. In humans, a disruptive NKAP variant has unmasked haemophilia A in a carrier by the same route. This explains the unaffected carrier state and predicts that NKAP variants can manifest in females only through what the skewing silences on the other X.
Animal models
Nkap mutant mouse (hemizygous males) Mouse recapitulates Heterozygous females reproduce the skewed X-inactivation documented in a human NKAP carrier.
Show evidence (2 references)
PMID:41828556 SUPPORT Model Organism
"Furthermore, these females exhibited significantly reduced F8 mRNA levels and FVIII (factor VIII) antigen levels, as demonstrated by quantitative RT-PCR and ELISA, respectively."
Shows the functional consequence of the skewing on a gene carried in cis with the mutant NKAP allele.
PMID:41828556 SUPPORT BACKGROUND Human Clinical
"We have previously reported that a disruptive NKAP mutation resulted in extremely skewed X chromosome inactivation (XCI), leading to phenotypic manifestation of hemophilia A (HA) in a HA carrier."
The human carrier observation that the model was built to explain.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hackmann-Di Donato Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Cardiovascular 3
Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (2 references)
PMID:38647244 SUPPORT Human Clinical
"An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD."
Prenatal congenital heart disease with a recurrent allele.
PMID:42481913 SUPPORT Human Clinical
"Unlike previously reported cases, our male index patient showed no cardiac malformation."
Records a case without a cardiac malformation, which is why the feature is frequent rather than constant.
Mitral valve prolapse FREQUENT HP:0001634 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral valve prolapse (HP:0001634). HP:0001634 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"| Mitral valve prolapse with associated regurgitation | 3 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
PMID:41917976 SUPPORT Human Clinical
"Regular cardiology follow-up with annual echocardiograms to monitor the mitral valve prolapse and aortic root diameter."
The later proband's own mitral valve prolapse, from his surveillance plan.
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38647244 SUPPORT Human Clinical
"During the second pregnancy, the mother conceived another male foetus exhibiting a ventricular septal defect for the second time (Figure 1D)."
Ventricular septal defect in both fetuses of the family.
PMID:41917976 SUPPORT Human Clinical
"| Atrial/ventricular septal defect | 2 | − |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Ear 1
Protruding ear VERY_FREQUENT HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large protruding ears, annotated with Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"| Large, protruding auricles | 9 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Genitourinary 2
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"| Cryptorchidism | 2 | − |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
PMID:41917976 SUPPORT Human Clinical
"| Abnormalities of the genitalia: | 5 | − |"
Count of the ten with any genital anomaly.
Hypospadias OCCASIONAL HP:0000047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypospadias (HP:0000047). HP:0000047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"| Hypospadias | 2 | − |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Head and Neck 6
Increased nuchal translucency HP:0010880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased nuchal translucency (HP:0010880). HP:0010880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38647244 SUPPORT Human Clinical
"In November 2021, a 29-year-old woman was admitted to Jinhua Maternal and Child Health Care Hospital due to her unborn child presenting with thickened nuchal translucency."
Single-fetus prenatal finding; no frequency is assigned.
Long face VERY_FREQUENT HP:0000276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long narrow face, annotated with Long face (HP:0000276). HP:0000276 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
Documented in the later proband.
PMID:41917976 SUPPORT Human Clinical
"| Narrow, elongated face | 8 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
High palate VERY_FREQUENT HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"| “Gothic” palate | 10 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Epicanthus VERY_FREQUENT HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"| Epicanthus | 9 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Midface retrusion FREQUENT HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface hypoplasia, annotated with Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"| Hypoplasia of the bottom half of the face | 7 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
PMID:41917976 SUPPORT Human Clinical
"Common clinical manifestations in individuals with NKAP mutations reported in the literature include the following: developmental delay, behavioral disturbances, muscle hypotonia, joint hypermobility, Marfanoid habitus with tall stature and arachnodactyly, and features of the following facial..."
The same paper's synthesis of the reported facial phenotype places the hypoplasia in the midface, which is the binding used here.
Short philtrum FREQUENT HP:0000322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short philtrum (HP:0000322). HP:0000322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"| Short philtrum | 7 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Limbs 1
Arachnodactyly VERY_FREQUENT HP:0001166 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arachnodactyly (HP:0001166). HP:0001166 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"arachnodactyly of the hands and feet"
Documented in the later proband.
PMID:41917976 SUPPORT Human Clinical
"| Arachnodactyly | 8 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Musculoskeletal 5
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle hypotonia, annotated with Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31587868 SUPPORT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
Hypotonia is listed among the conserved core features.
Joint hypermobility VERY_FREQUENT HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"joint hypermobility, habitual dislocation of the right shoulder joint"
Documented in the later proband.
PMID:41917976 SUPPORT Human Clinical
"| Joint hypermobility | 9 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31587868 SUPPORT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
Scoliosis is listed among the conserved core features.
PMID:41917976 SUPPORT Human Clinical
"| Scoliosis | 6 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Pectus deformity FREQUENT Abnormal sternum morphology HP:0000766 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum or carinatum, annotated with Abnormal sternum morphology (HP:0000766). HP:0000766 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"scoliosis of the lumbar spine, moderate pectoral deformity, plano-valgus position of the feet"
Documented in the later proband.
PMID:41917976 SUPPORT Human Clinical
"| Pectoral deformity (pectus excavatum/pectus carinatum) | 5 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Joint contractures FREQUENT HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contractures, annotated with Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31587868 SUPPORT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
Joint contractures are listed among the conserved core features.
PMID:41917976 SUPPORT Human Clinical
"| Camptodactyly | 4 | − |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Nervous System 5
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31587868 SUPPORT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
Developmental delay is listed among the conserved core features.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42481913 SUPPORT Human Clinical
"Hackmann-Di Donato syndrome is an X-linked neurodevelopmental disorder characterized by intellectual disability, developmental delay, dysmorphic features, marfanoid habitus, and hypotonia."
Names intellectual disability as a defining feature.
PMID:41917976 SUPPORT Human Clinical
"elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
Documents the mild end of the cognitive spectrum in a proband with an exon 4 variant of uncertain significance.
Aggressive behavior FREQUENT HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31587868 SUPPORT INDIRECT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
The abstract records behavioural abnormalities as a core feature.
PMID:41917976 SUPPORT Human Clinical
"| Aggressive behavior | 5 | − |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
Abnormal cerebral white matter Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral white matter lesions, annotated with Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42481913 SUPPORT Human Clinical
"Brain MRI revealed stable white matter lesions."
Single-case neuroimaging finding.
Absence seizures Generalized non-motor (absence) seizure HP:0002121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absence seizures, annotated with Generalized non-motor (absence) seizure (HP:0002121). HP:0002121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
Single-case finding in a proband whose variant is classified as uncertain.
Growth 2
Marfanoid habitus VERY_FREQUENT Disproportionate tall stature HP:0001519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Marfanoid habitus, annotated with Disproportionate tall stature (HP:0001519). HP:0001519 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31587868 SUPPORT Human Clinical
"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
Marfanoid habitus is listed among the conserved core features.
PMID:41917976 SUPPORT Human Clinical
"presented with a Marfanoid habitus, tall stature, dolichostenomelia, scoliosis of the lumbar spine"
Documents the habitus in a later proband.
Tall stature VERY_FREQUENT HP:0000098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall stature (HP:0000098). HP:0000098 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41917976 SUPPORT Human Clinical
"presented with a Marfanoid habitus, tall stature, dolichostenomelia, scoliosis of the lumbar spine"
Documented in the later proband.
PMID:41917976 SUPPORT Human Clinical
"| Tall stature | 10 | + |"
Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
🧬

Genetic Associations

1
NKAP
Gene: NKAP hgnc:29873 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NKAP (hgnc:29873). hgnc:29873 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:31587868 SUPPORT Human Clinical
"Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP."
Original gene-disease report.
PMID:42481913 SUPPORT Human Clinical
"Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature."
Sizes the reported cohort as of 2026.
Variants (2)
p.Arg330Cys Likely Pathogenic
NM_024528.4:c.988C>T, p.Arg330Cys. Reported in the original cohort and in two fetuses with congenital heart defects; in transfected HEK293T cells it lowers NKAP transcript but not protein, alters intranuclear distribution and reduces HDAC3 binding. Proposed for reclassification as likely pathogenic. All four individuals with a p.Arg330 variant reported to 2024 had a cardiac defect.
Show evidence (2 references)
PMID:38647244 SUPPORT Human Clinical
"An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD."
Identifies the allele in two fetuses.
PMID:38647244 SUPPORT In Vitro
"Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD."
Functional evidence behind the likely-pathogenic call.
p.Arg204Ser Uncertain Significance
ENST00000371410.5:c.612A>C, p.Arg204Ser in exon 4, outside the exon 8-9 cluster, found by whole-genome sequencing in a 12-year-old with the full Marfanoid-intellectual disability picture. Classified as a variant of uncertain significance; its pathogenicity requires further analysis.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"The pathogenicity of the nucleotide variant of exon 4 of NKAP requires further analysis."
The authors' own classification of the variant.
💊

Medical Actions

3
Genetic counselling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
X-linked recessive counselling for the family, including carrier testing of the mother and at-risk female relatives; familial transmission is documented.
Show evidence (1 reference)
PMID:42481913 SUPPORT INDIRECT Human Clinical
"Among these cases, evidence of familial transmission has been documented in five individuals from three unrelated families."
Documented inherited cases are the basis for counselling and carrier testing.
Multidisciplinary supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
No disease-specific therapy exists. Management is supportive and follows the case-level surveillance plan given to one reported proband: regular cardiology follow-up with annual echocardiography for mitral valve prolapse and aortic root diameter, orthopaedic care with physical therapy for scoliosis, joint hypermobility and recurrent dislocation, neurological follow-up with EEG where epilepsy is present (the proband's absence epilepsy was treated with ethosuximide), ophthalmological examination, and neuropsychological assessment with ongoing educational support.
Show evidence (4 references)
PMID:41917976 SUPPORT Human Clinical
"Regular cardiology follow-up with annual echocardiograms to monitor the mitral valve prolapse and aortic root diameter."
Cardiac surveillance element of the single-proband plan.
PMID:41917976 SUPPORT Human Clinical
"Orthopedic care for scoliosis, joint hypermobility, and habitual dislocation, including physical therapy."
Orthopaedic element of the single-proband plan.
PMID:41917976 SUPPORT Human Clinical
"Continued neurology management with routine electroencephalography (EEG) monitoring to manage his absence epilepsy."
Neurological element of the single-proband plan.
+ 1 more reference
Ethosuximide for absence epilepsy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ethosuximide CHEBI:4887 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethosuximide (CHEBI:4887). CHEBI:4887 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
In the one proband with absence epilepsy, seizures were treated with valproic acid and ethosuximide from age 5, valproate was withdrawn at 6, and remission has been maintained on ethosuximide since age 11. Single-case management of a feature not confirmed as part of the syndrome.
Target Phenotypes: Absence seizures HP:0002121 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Absence seizures, annotated with Generalized non-motor (absence) seizure (HP:0002121). HP:0002121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41917976 SUPPORT Human Clinical
"Remission has been maintained since the age of 11 years, and the patient is currently receiving 1000 mg/day of ethosuximide."
Single-case treatment and outcome.
🔬

Diagnosis

1
Exome or genome sequencing
Diagnosis rests on identifying a hemizygous NKAP missense variant, in practice by trio exome or whole-genome sequencing, in a male with intellectual disability and a Marfanoid habitus. The clinical picture overlaps the broadly defined Lujan-Fryns phenotype, and an NKAP variant was found in one of 28 males with that tentative diagnosis.
trio exome or genome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:42481913 SUPPORT Human Clinical
"Here, we present a further familial case of Hackmann-Di Donato syndrome involving an inherited pathogenic NKAP variant, identified through trio exome sequencing."
Trio exome sequencing as the diagnostic route.
PMID:41917976 SUPPORT Human Clinical
"Additionally, the case illustrates the need to test male patients with a Marfanoid phenotype and intellectual disability for mutations in NKAP."
States the clinical indication for NKAP testing.
PMID:26358559 SUPPORT Human Clinical
"X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each."
Places NKAP in the differential of the Lujan-Fryns phenotype before the syndrome was delineated.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Twelve individuals with pathogenic NKAP variants had been reported before the 2026 familial case; with that case and a 2026 proband carrying a variant of uncertain significance, about fourteen individuals are known.
Show evidence (1 reference)
PMID:42481913 SUPPORT Human Clinical
"Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature."
Literature case count as of 2026.
🧫

Experimental Models

1
HEK293T cells expressing NKAP p.Arg330Cys CELL_LINE
Transient expression of the recurrent patient allele in HEK293T cells.
Publication
PMID:38647244
Pathograph links
Loss of NKAP-HDAC3 Corepressor Complex Function recapitulates fidelity: moderate observes: molecular Shows reduced HDAC3 binding and altered intranuclear distribution of the mutant protein.
Limitations: Overexpression in a non-neural, non-cardiac cell line; endogenous dosage and cell-type context are not modelled.
Show evidence (1 reference)
PMID:38647244 SUPPORT In Vitro
"Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3."
The measurements made in this system.
Show evidence (1 reference)
PMID:38647244 SUPPORT In Vitro
"Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level."
Establishes the transfection system and its first readout.
🐁

Animal Models

2
nkap C-terminal truncation zebrafish
Zebrafish carrying a C-terminally truncated nkap allele show severe developmental defects.
Species
Zebrafish
Genotype
nkap mutant with C-terminally truncated NKAP
Publication
PMID:31587868
Pathograph links
NKAP C-terminal Missense Variant perturbs fidelity: low observes: organism Removes the C-terminal region in which the human missense variants cluster and produces developmental defects; it perturbs the region rather than reproducing a missense lesion.
Limitations: The allele is a truncation removing the C-terminal region, not a missense change within it, so it may behave as a null where the human alleles retain protein; the developmental phenotype is not resolved into the human neurodevelopmental or skeletal features.
Show evidence (1 reference)
PMID:31587868 SUPPORT Model Organism
"Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects."
The authors use the model to support the C-terminal region's developmental role, which is the node it is linked to.
Show evidence (1 reference)
PMID:31587868 SUPPORT Model Organism
"Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects."
Establishes the model and its developmental phenotype.
Nkap mutant mouse (hemizygous males)
CRISPR/Cas9-generated in-frame deletion in the N-terminal RS domain, not the C-terminal region mutated in humans. Hemizygous males show altered gait on CatWalk analysis, read by the authors as consistent with the hypotonia of affected humans, but normal weight and size and normal bone length and structure on X-ray, so the Marfanoid skeletal phenotype is not reproduced. Embryonic fibroblasts from mutant embryos proliferate poorly and senesce, and heterozygous females show skewed X-inactivation against the mutant allele.
Species
Mouse
Genotype
Nkap c.5_127del (p.Ala2_Gly43del), in-frame 123 bp deletion in exon 1 (N-terminal RS domain), hemizygous males
Publication
PMID:41828556
Pathograph links
Impaired Neurodevelopment partially recapitulates fidelity: low observes: organism Gait alteration is the only neurological readout and is interpreted as a hypotonia correlate.
Limitations: Gait parameters are an indirect proxy for hypotonia; cognition was not assessed, and the engineered allele is described as deleterious rather than matching a patient missense variant.
Readouts
CatWalk XT gait parameters
Direction: ALTERED
Interpretation: Motor correlate of the hypotonia seen in affected males.
Show evidence (1 reference)
PMID:41828556 SUPPORT Model Organism
"Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
Reports the gait measurement.
Show evidence (1 reference)
PMID:41828556 SUPPORT INDIRECT Model Organism
"Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
The authors read the gait change as a hypotonia correlate; that it reflects a neurodevelopmental defect is their inference and ours.
Reduced Cellular Proliferation and Senescence recapitulates fidelity: unknown observes: cellular Embryonic fibroblasts from this model are the source of the proliferation and senescence observation.
Limitations: The allele is an N-terminal in-frame deletion, so the result shows what a deleterious Nkap allele does to mouse cells, not what the human C-terminal missense alleles do; fidelity to the human disease is unknown.
Show evidence (1 reference)
PMID:41828556 SUPPORT In Vitro
"Murine embryonic fibroblasts (MEFs) derived from a hemizygous mutant NKAP embryo exhibited markedly reduced proliferation rate and increased senescence compared to WT NKAP MEFs"
The measurement made in cells derived from this model.
Skewed X-Inactivation in Heterozygous Females recapitulates fidelity: moderate observes: organism Heterozygous females reproduce the skewed X-inactivation documented in a human NKAP carrier.
Show evidence (1 reference)
PMID:41828556 SUPPORT Model Organism
"XCI pattern analysis using methylation-sensitive restriction enzymes demonstrated that mutant NKAP/HA females exhibited significant XCI skewing of the X chromosome bearing the mutant NKAP copy."
The skewing is measured directly in the model.
Show evidence (1 reference)
PMID:41828556 SUPPORT Model Organism
"Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
Establishes the model and its motor phenotype.
{ }

Source YAML

click to show 
name: Hackmann-Di Donato Syndrome
creation_date: "2026-10-15T18:30:00Z"
category: Mendelian
description: >-
  Hackmann-Di Donato syndrome (MRXSHD) is an X-linked syndromic intellectual
  developmental disorder caused by hemizygous missense variants in NKAP, which
  encodes NF-kappa-B activating protein, a ubiquitously expressed nucleoplasmic
  transcriptional regulator that acts in an HDAC3-containing corepressor complex
  and associates with the post-catalytic spliceosome. The reported variants
  cluster in the C-terminal region that mediates those interactions. Affected
  males show a highly conserved picture of developmental delay and intellectual
  disability, hypotonia, a Marfanoid habitus with tall stature, arachnodactyly
  and joint hypermobility, scoliosis, joint contractures, behavioural
  abnormalities, a recognisable facial gestalt (long face, high palate, large
  protruding ears, epicanthus, short philtrum) and, in a majority, congenital
  cardiovascular anomalies. Fewer than twenty affected individuals have been
  reported, including two fetuses ascertained through severe congenital heart
  defects. Patient-derived cells carry a transcriptome signature of downregulated
  long, exon-rich genes, which is the mechanistic basis currently proposed.
synonyms:
- intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type
- Hackman-Di Donato syndrome
- NKAP-related syndrome
- NKAP-related syndromic intellectual disability
- MRXSHD
disease_term:
  preferred_term: Hackmann-Di Donato syndrome
  term:
    id: MONDO:0026733
    label: intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type
parents:
- X-linked syndromic intellectual disability
notes: >-
  No GeneReviews or StatPearls chapter exists for this disorder (Bookshelf index
  snapshot 2026-09-10). ClinGen has not published a gene-disease validity
  classification for NKAP (gene_validity export pinned 2026-10-04 in
  data/clingen/MANIFEST.yaml), so gene_disease_validity is absent. The
  phenotype frequencies in this entry are those of the ten affected males of
  the original cohort (Fiordaliso et al. 2019), as tabulated against a later
  proband by Semyachkina et al. 2026, whose comparison table is quoted as the
  evidence for each count. The condition sits in the differential of
  Lujan-Fryns syndrome: an NKAP variant was found by X-exome sequencing in one
  of 28 males carrying a tentative clinical diagnosis of Lujan-Fryns syndrome
  before the syndrome was delineated.
inheritance:
- name: X-linked recessive
  description: >-
    Hemizygous males are affected. Familial transmission from unaffected or
    much less severely affected heterozygous mothers has been documented in
    several families; the remaining cases in the original cohort were apparently
    de novo, and one pair of affected brothers born to an unaffected mother
    indicates maternal germline mosaicism, so an apparently de novo case still
    carries a recurrence risk. In a mouse
    model, females heterozygous for a deleterious Nkap allele show extreme
    skewing of X-chromosome inactivation against the mutant-bearing X, which
    offers a mechanism for the unaffected carrier state; the same phenomenon has
    unmasked haemophilia A in a human carrier of a disruptive NKAP variant.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these cases, evidence of familial transmission has been documented in five individuals from three unrelated families."
    explanation: Documents inherited (maternal) transmission consistent with X-linked recessive inheritance.
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "XCI pattern analysis using methylation-sensitive restriction enzymes demonstrated that mutant NKAP/HA females exhibited significant XCI skewing of the X chromosome bearing the mutant NKAP copy."
    explanation: Shows in mice that the mutant-NKAP X is preferentially inactivated in heterozygous females, explaining why carrier females are unaffected.
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "We have previously reported that a disruptive NKAP mutation resulted in extremely skewed X chromosome inactivation (XCI), leading to phenotypic manifestation of hemophilia A (HA) in a HA carrier."
    explanation: The human observation of NKAP-driven X-inactivation skewing in a heterozygous female, restated in this paper's introduction.
pathophysiology:
- name: NKAP C-terminal Missense Variant
  biological_scale: MOLECULAR
  description: >-
    Hemizygous missense variants in NKAP, clustered in exons 8 and 9 encoding the
    conserved C-terminal (DUF926) region through which NKAP binds HDAC3 and
    post-catalytic spliceosomal proteins. Reported alleles include p.Arg330Cys,
    p.Arg330His, p.Arg333Gln, p.Ile337Thr and p.Arg361Gln. One proband carried an
    exon 4 variant (p.Arg204Ser) of uncertain significance, which, if confirmed,
    would widen the mutational spectrum beyond the C-terminal cluster.
  genes:
  - preferred_term: NKAP
    term:
      id: hgnc:29873
      label: NKAP
  molecular_functions:
  - preferred_term: transcription corepressor activity
    term:
      id: GO:0003714
      label: transcription corepressor activity
    modifier: DECREASED
  - preferred_term: histone deacetylase binding
    term:
      id: GO:0042826
      label: histone deacetylase binding
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    description: >-
      Hemizygous missense alleles in males. The functional category is not
      established: transfected p.Arg330Cys lowers NKAP transcript but not protein
      and disturbs HDAC3 binding and intranuclear distribution, consistent with a
      partial loss of corepressor function rather than a null.
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins."
    explanation: Establishes the C-terminal clustering of the causal missense variants and the interaction surfaces they fall on.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "All previously reported patients had mutations located in exons 8 and 9 of NKAP."
    explanation: Localises the established variant cluster to exons 8 and 9.
  downstream:
  - target: Loss of NKAP-HDAC3 Corepressor Complex Function
    causal_link_type: DIRECT
    description: The recurrent p.Arg330Cys allele disturbs NKAP binding to HDAC3 and its intranuclear distribution.
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3."
      explanation: Directly links a patient allele to loss of the HDAC3 interaction in transfected cells.
  - target: Perturbed Spliceosomal Exon-Ligation Association
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The variant cluster lies in the region that contacts the post-catalytic
      spliceosome; a functional consequence for splicing is inferred, not yet shown.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins."
      explanation: The spliceosome-contacting region is the one mutated; the step from location to functional perturbation is an inference.
  - target: Reduced Cellular Proliferation and Senescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown only for a mouse allele that is an in-frame 123 bp deletion in exon
      1 (N-terminal RS domain), not a C-terminal missense change; whether the
      human alleles produce the same cellular defect is untested.
    evidence:
    - reference: PMID:41828556
      reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Murine embryonic fibroblasts (MEFs) derived from a hemizygous mutant NKAP embryo exhibited markedly reduced proliferation rate and increased senescence compared to WT NKAP MEFs"
      explanation: A deleterious Nkap allele produces the defect in primary mouse cells; the inference to the human C-terminal missense alleles is the step not yet made.
- name: Loss of NKAP-HDAC3 Corepressor Complex Function
  biological_scale: MOLECULAR
  description: >-
    NKAP is a transcriptional repressor that associates with histone deacetylase 3
    and with the Notch corepressor complex, and it must bind HDAC3 to act in T
    cell maturation and haematopoietic stem cell survival. Mutant NKAP loses
    HDAC3 binding and mislocalises within the nucleus, so corepressor activity at
    NKAP target genes, including Notch targets, is expected to fall.
  molecular_functions:
  - preferred_term: transcription corepressor activity
    term:
      id: GO:0003714
      label: transcription corepressor activity
    modifier: DECREASED
  - preferred_term: histone deacetylase binding
    term:
      id: GO:0042826
      label: histone deacetylase binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: negative regulation of Notch signaling pathway
    term:
      id: GO:0045746
      label: negative regulation of Notch signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:19409814
    reference_title: "NKAP is a transcriptional repressor of notch signaling and is required for T cell development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "NKAP associated with the histone deacetylase HDAC3 and was shown to be part of a DNA-binding complex, as demonstrated by chromatin immunoprecipitation. NKAP also associated with the Notch corepressor complex."
    explanation: Defines the HDAC3 and Notch-corepressor interactions of wild-type NKAP that the C-terminal variants disturb; the disease relevance is inferred.
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level."
    explanation: Shows the recurrent allele does not abolish the protein, supporting a qualitative loss of complex function rather than absence.
  downstream:
  - target: Dysregulated Cardiac Morphogenesis Gene Expression
    causal_link_type: DIRECT
    description: >-
      The authors attribute the cardiac gene dysregulation produced by p.Arg330Cys
      to the allele's altered intranuclear distribution and obstructed HDAC3
      binding.
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD."
      explanation: States the causal route from lost HDAC3 interaction to cardiac gene dysregulation.
  - target: Transcriptional Dysregulation of Long Exon-rich Genes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of corepressor function is the proposed route to the patient transcriptome signature.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins."
      explanation: Frames NKAP's transcriptional role as HDAC3-dependent, which is the basis for reading the signature as a corepressor defect.
- name: Perturbed Spliceosomal Exon-Ligation Association
  biological_scale: MOLECULAR
  description: >-
    NKAP is a nuclear speckle protein that, with CACTIN and SDE2, stabilises the
    catalytic conformation of the human post-catalytic spliceosome during exon
    ligation. The disease variants fall in the region that mediates this
    association, so a splicing contribution to the transcriptome signature is
    plausible but has not been demonstrated in patient cells.
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:30705154
    reference_title: "A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "CACTIN, SDE2, and NKAP-factors implicated in alternative splicing-further stabilize the catalytic conformation of the spliceosome during exon ligation."
    explanation: Structural evidence for NKAP's role in exon ligation in the wild-type spliceosome; the effect of the disease alleles is inferred.
  downstream:
  - target: Transcriptional Dysregulation of Long Exon-rich Genes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A defect in exon ligation would be expected to bear hardest on long genes
      with many exons, which is the class the patient signature downregulates.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers."
      explanation: The exon-number dependence of the signature is the observation that makes a splicing contribution plausible; it does not prove it.
- name: Transcriptional Dysregulation of Long Exon-rich Genes
  biological_scale: CELLULAR
  description: >-
    Transcriptome analysis of cells from affected individuals shows a distinctive
    signature in which long genes with higher exon numbers are downregulated.
    This is the defining cellular phenotype of the disorder and the reason it is
    described as a disorder of transcriptional regulation.
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers."
    explanation: Direct report of the transcriptome signature in affected individuals.
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Perturbation of the NKAP C-terminal region produces developmental defects
      in humans and zebrafish; which dysregulated transcripts drive the
      neurodevelopmental phenotype is not known.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish."
      explanation: Connects the transcriptional defect to developmental consequences without resolving the intermediates.
  - target: Abnormal Skeletal and Connective Tissue Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The Marfanoid skeletal picture is attributed to the same transcriptional
      defect; no connective-tissue target gene has been identified.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish."
      explanation: The skeletal features are part of the developmental defects the paper attributes to the transcriptional disorder.
- name: Dysregulated Cardiac Morphogenesis Gene Expression
  biological_scale: CELLULAR
  description: >-
    NKAP p.Arg330Cys dysregulates transcription of cardiac morphogenesis genes
    including DHRS3, DNAH11 and JAG1, which the authors attribute to lost HDAC3
    binding and mislocalisation of the mutant protein, offering a route to the
    congenital heart defects seen in a majority of affected males and in both
    reported fetuses. DHRS3 moved in the opposite direction in patient
    lymphoblastoid cells, so the direction of individual gene changes is not
    settled.
  biological_processes:
  - preferred_term: heart morphogenesis
    term:
      id: GO:0003007
      label: heart morphogenesis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1."
    explanation: Reports the cardiac developmental gene dysregulation produced by the patient allele.
  downstream:
  - target: Congenital heart defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Proposed explanation for the fetal and postnatal cardiac malformations.
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD."
      explanation: The same allele studied in vitro was found in fetuses with congenital heart disease; causation of the malformation by the transcriptional change is inferred.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors' proposed route from p.Arg330Cys to the septal and outflow malformations seen in the fetuses.
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "R330C-induced CHD: the mutation alters Nkap protein intra-nuclear distribution and inhibits its binding to Hdac3 protein, thereby disrupting the transcription of cardiac development-related genes and ultimately leading to CHD, manifested as ventricular septal defect, overriding aorta and pulmonary stenosis (Figure 4C)."
      explanation: The authors' model statement; the last step to the malformation is inferred from the in vitro result.
- name: Impaired Neurodevelopment
  biological_scale: TISSUE
  description: >-
    NKAP is highly expressed in neural progenitor cells and migrating neuroblasts
    of the mammalian subventricular zone and in mature neurons of several regions,
    and the syndrome is grouped with the nuclear speckleopathies, in which
    developmental disability is the shared feature. The neuroanatomical basis of
    the intellectual disability is largely unexamined; white matter lesions were
    found in one familial case.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24583034
    reference_title: "The Notch co-repressor protein NKAP is highly expressed in adult mouse subventricular zone neural progenitor cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "NKAP is highly expressed in Mash1(+) transit amplifying cells and PSA-NCAM(+) migrating neuroblasts throughout the subventricular zone (SVZ) and the rostral migratory stream (RMS), as well as in the hippocampus."
    explanation: Expression in neurogenic progenitors makes neurodevelopment a plausible site of action; it does not itself show a defect.
  - reference: PMID:36929417
    reference_title: "Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development."
    explanation: Places NKAP-related syndrome among the nuclear speckleopathies whose shared feature is developmental disability.
  downstream:
  - target: Global developmental delay
  - target: Intellectual disability
  - target: Hypotonia
  - target: Aggressive behavior
  - target: Abnormal cerebral white matter
    causal_link_type: UNKNOWN
- name: Abnormal Skeletal and Connective Tissue Development
  biological_scale: TISSUE
  description: >-
    Affected males have a Marfanoid habitus with tall stature, long limbs,
    arachnodactyly, joint hypermobility, pectus deformity, scoliosis and joint
    contractures. The connective-tissue mechanism is unknown; FBN1-independent
    Marfanoid phenotypes with intellectual disability are a recognised group that
    also includes Lujan-Fryns syndrome.
  evidence:
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Males with missense NKAP mutations have been reported to present with marfanoid features and behavioral and musculoskeletal abnormalities."
    explanation: Summarises the musculoskeletal and Marfanoid picture of affected males.
  downstream:
  - target: Marfanoid habitus
  - target: Tall stature
  - target: Arachnodactyly
  - target: Joint hypermobility
  - target: Scoliosis
  - target: Pectus deformity
  - target: Joint contractures
- name: Reduced Cellular Proliferation and Senescence
  biological_scale: CELLULAR
  description: >-
    Embryonic fibroblasts hemizygous for a deleterious Nkap allele show markedly
    reduced proliferation and increased senescence. In heterozygous females this
    confers a growth disadvantage on cells whose active X carries the mutant
    allele, producing the extreme X-inactivation skewing seen in carriers.
    Whether the human missense alleles reproduce this is untested; complete NKAP
    loss causes R-loop accumulation and genome instability in cell lines.
  cell_types:
  - preferred_term: embryonic fibroblast
    term:
      id: CL:2000042
      label: embryonic fibroblast
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DECREASED
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  evidence:
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Murine embryonic fibroblasts (MEFs) derived from a hemizygous mutant NKAP embryo exhibited markedly reduced proliferation rate and increased senescence compared to WT NKAP MEFs"
    explanation: Direct measurement of the proliferation and senescence defect in mutant cells.
  - reference: PMID:37322264
    reference_title: "NKAP acts with HDAC3 to prevent R-loop associated genome instability."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Here, we show that NKAP (NF-κB activating protein) is essential for preventing R-loop accumulation and maintaining genome integrity through forming a protein complex with HDAC3."
    explanation: NKAP depletion in cell lines causes R-loop-associated genome instability, a candidate basis for the proliferation defect; the study used depletion, not patient alleles.
  downstream:
  - target: Skewed X-Inactivation in Heterozygous Females
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Secondary selection against cells expressing the mutant allele.
    evidence:
    - reference: PMID:41828556
      reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "XCI pattern analysis using methylation-sensitive restriction enzymes demonstrated that mutant NKAP/HA females exhibited significant XCI skewing of the X chromosome bearing the mutant NKAP copy."
      explanation: The skewing is observed in the same model whose mutant cells proliferate poorly; the authors propose secondary selection as the link.
- name: Skewed X-Inactivation in Heterozygous Females
  biological_scale: ORGANISM
  description: >-
    Heterozygous female mice preferentially inactivate the X bearing the mutant
    Nkap allele, and in a double-mutant model this silences a wild-type F8 allele
    in cis, reducing factor VIII. In humans, a disruptive NKAP variant has unmasked
    haemophilia A in a carrier by the same route. This explains the unaffected
    carrier state and predicts that NKAP variants can manifest in females only
    through what the skewing silences on the other X.
  evidence:
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, these females exhibited significantly reduced F8 mRNA levels and FVIII (factor VIII) antigen levels, as demonstrated by quantitative RT-PCR and ELISA, respectively."
    explanation: Shows the functional consequence of the skewing on a gene carried in cis with the mutant NKAP allele.
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "We have previously reported that a disruptive NKAP mutation resulted in extremely skewed X chromosome inactivation (XCI), leading to phenotypic manifestation of hemophilia A (HA) in a HA carrier."
    explanation: The human carrier observation that the model was built to explain.
phenotypes:
- name: Global developmental delay
  category: Neurological
  frequency: VERY_FREQUENT
  description: Present in all ten males of the original cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: Developmental delay is listed among the conserved core features.
- name: Intellectual disability
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability or developmental delay was present in all ten males
    of the original cohort; severity ranges down to borderline intelligence in
    one later proband.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hackmann-Di Donato syndrome is an X-linked neurodevelopmental disorder characterized by intellectual disability, developmental delay, dysmorphic features, marfanoid habitus, and hypotonia."
    explanation: Names intellectual disability as a defining feature.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
    explanation: Documents the mild end of the cognitive spectrum in a proband with an exon 4 variant of uncertain significance.
- name: Hypotonia
  category: Neurological
  frequency: VERY_FREQUENT
  description: Muscle hypotonia in all ten males of the original cohort and in later probands.
  phenotype_term:
    preferred_term: Muscle hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: Hypotonia is listed among the conserved core features.
- name: Aggressive behavior
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Behavioural abnormalities are a core feature; aggressive behaviour specifically
    was recorded in five of the ten males of the original cohort.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: The abstract records behavioural abnormalities as a core feature.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Aggressive behavior | 5 | − |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Marfanoid habitus
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Disproportionate tall stature with long limbs (dolichostenomelia) and a slender build, present in essentially all affected males.
  phenotype_term:
    preferred_term: Marfanoid habitus
    term:
      id: HP:0001519
      label: Disproportionate tall stature
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: Marfanoid habitus is listed among the conserved core features.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with a Marfanoid habitus, tall stature, dolichostenomelia, scoliosis of the lumbar spine"
    explanation: Documents the habitus in a later proband.
- name: Tall stature
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Recorded in all ten males of the original cohort.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with a Marfanoid habitus, tall stature, dolichostenomelia, scoliosis of the lumbar spine"
    explanation: Documented in the later proband.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Tall stature | 10 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Arachnodactyly
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Long slender fingers and toes in eight of ten males of the original cohort.
  phenotype_term:
    preferred_term: Arachnodactyly
    term:
      id: HP:0001166
      label: Arachnodactyly
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arachnodactyly of the hands and feet"
    explanation: Documented in the later proband.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Arachnodactyly | 8 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Joint hypermobility
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Present in nine of ten males of the original cohort; habitual shoulder dislocation was reported in one later proband.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joint hypermobility, habitual dislocation of the right shoulder joint"
    explanation: Documented in the later proband.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Joint hypermobility | 9 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Scoliosis
  category: Musculoskeletal
  frequency: FREQUENT
  description: Scoliosis in six of ten males of the original cohort.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: Scoliosis is listed among the conserved core features.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Scoliosis | 6 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Pectus deformity
  category: Musculoskeletal
  frequency: FREQUENT
  description: Pectus excavatum or pectus carinatum in five of ten males of the original cohort.
  phenotype_term:
    preferred_term: Pectus excavatum or carinatum
    term:
      id: HP:0000766
      label: Abnormal sternum morphology
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "scoliosis of the lumbar spine, moderate pectoral deformity, plano-valgus position of the feet"
    explanation: Documented in the later proband.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Pectoral deformity (pectus excavatum/pectus carinatum) | 5 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Joint contractures
  category: Musculoskeletal
  frequency: FREQUENT
  description: Joint contractures, chiefly camptodactyly, in four of ten males of the original cohort.
  phenotype_term:
    preferred_term: Joint contractures
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis."
    explanation: Joint contractures are listed among the conserved core features.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Camptodactyly | 4 | − |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Congenital heart defect
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Cardiovascular anomalies in seven of ten males of the original cohort (atrial
    or ventricular septal defect, patent ductus arteriosus, aortic dilatation,
    mitral valve prolapse) and severe congenital heart defects in both reported
    fetuses with p.Arg330Cys. One later familial case had no cardiac
    malformation.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD."
    explanation: Prenatal congenital heart disease with a recurrent allele.
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike previously reported cases, our male index patient showed no cardiac malformation."
    explanation: Records a case without a cardiac malformation, which is why the feature is frequent rather than constant.
- name: Mitral valve prolapse
  category: Cardiovascular
  frequency: FREQUENT
  description: Mitral valve prolapse with regurgitation in three of ten males of the original cohort and in the later proband; the most frequent individual cardiac finding.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Mitral valve prolapse with associated regurgitation | 3 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular cardiology follow-up with annual echocardiograms to monitor the mitral valve prolapse and aortic root diameter."
    explanation: The later proband's own mitral valve prolapse, from his surveillance plan.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    Both reported fetuses carrying p.Arg330Cys had a ventricular septal defect,
    the first with pulmonary stenosis and an overriding aorta suggesting a
    tetralogy of Fallot-like malformation; a septal defect was recorded in two
    of ten males of the original cohort. No frequency is assigned because the
    fetal ascertainment was through the heart defect itself.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the second pregnancy, the mother conceived another male foetus exhibiting a ventricular septal defect for the second time (Figure 1D)."
    explanation: Ventricular septal defect in both fetuses of the family.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Atrial/ventricular septal defect | 2 | − |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Increased nuchal translucency
  category: Prenatal
  description: Thickened nuchal translucency at 12 weeks of gestation was the presenting prenatal finding in the first reported fetus.
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
  evidence:
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In November 2021, a 29-year-old woman was admitted to Jinhua Maternal and Child Health Care Hospital due to her unborn child presenting with thickened nuchal translucency."
    explanation: Single-fetus prenatal finding; no frequency is assigned.
- name: Cryptorchidism
  category: Genitourinary
  frequency: OCCASIONAL
  description: Two of ten males of the original cohort; genital anomalies of any kind (cryptorchidism, hypospadias or micropenis) were present in five of ten.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Cryptorchidism | 2 | − |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Abnormalities of the genitalia: | 5 | − |"
    explanation: Count of the ten with any genital anomaly.
- name: Hypospadias
  category: Genitourinary
  frequency: OCCASIONAL
  description: Two of ten males of the original cohort.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hypospadias | 2 | − |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Long face
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Narrow, elongated face in eight of ten males of the original cohort.
  phenotype_term:
    preferred_term: Long narrow face
    term:
      id: HP:0000276
      label: Long face
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
    explanation: Documented in the later proband.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Narrow, elongated face | 8 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: High palate
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: High-arched ("Gothic") palate in all ten males of the original cohort.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| “Gothic” palate | 10 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Protruding ear
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Large, protruding auricles in nine of ten males of the original cohort.
  phenotype_term:
    preferred_term: Large protruding ears
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Large, protruding auricles | 9 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Epicanthus
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Epicanthal folds in nine of ten males of the original cohort.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Epicanthus | 9 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Midface retrusion
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Midface hypoplasia, part of the long narrow face, in seven of ten males of
    the original cohort. The comparison table words the same feature as
    hypoplasia of the bottom half of the face; the paper's synthesis of the
    facial phenotype calls it hypoplasia of the midsection, which is followed
    here.
  phenotype_term:
    preferred_term: Midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hypoplasia of the bottom half of the face | 7 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical manifestations in individuals with NKAP mutations reported in the literature include the following: developmental delay, behavioral disturbances, muscle hypotonia, joint hypermobility, Marfanoid habitus with tall stature and arachnodactyly, and features of the following facial phenotype: epicanthus, long narrow face with hypoplasia of the midsection, short philtrum, and dysplastic ears."
    explanation: The same paper's synthesis of the reported facial phenotype places the hypoplasia in the midface, which is the binding used here.
- name: Short philtrum
  category: Craniofacial
  frequency: FREQUENT
  description: Short philtrum in seven of ten males of the original cohort.
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Short philtrum | 7 | + |"
    explanation: Row of the comparison table of the ten previously reported males (Fiordaliso et al. 2019) against the later proband; the number is the count of those ten with the feature.
- name: Abnormal cerebral white matter
  category: Neurological
  description: >-
    Stable white matter lesions on brain MRI in one familial case. Neuroimaging
    has not been systematically assessed in reported cases, so no frequency is
    assigned.
  phenotype_term:
    preferred_term: Cerebral white matter lesions
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed stable white matter lesions."
    explanation: Single-case neuroimaging finding.
- name: Absence seizures
  category: Neurological
  description: >-
    Absence epilepsy in one proband carrying an exon 4 variant of uncertain
    significance; epilepsy was absent from all ten males of the original cohort,
    so this feature is unconfirmed as part of the syndrome and no frequency is
    assigned.
  phenotype_term:
    preferred_term: Absence seizures
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elongated face, muscle hypotonia, absence epilepsy, and borderline intelligence"
    explanation: Single-case finding in a proband whose variant is classified as uncertain.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twelve individuals with pathogenic NKAP variants had been reported before
    the 2026 familial case; with that case and a 2026 proband carrying a variant
    of uncertain significance, about fourteen individuals are known.
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature."
    explanation: Literature case count as of 2026.
genetic:
- name: NKAP
  gene_term:
    preferred_term: NKAP
    term:
      id: hgnc:29873
      label: NKAP
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    NKAP (Xq24) encodes NF-kappa-B activating protein, a 415-residue nuclear
    speckle protein with an N-terminal RS domain and a C-terminal DUF926 domain.
    All established disease variants are hemizygous missense changes in exons 8
    and 9, within the C-terminal region that binds HDAC3 and the post-catalytic
    spliceosome. The gene-disease relationship rests on a cohort of ten males
    from eight families with clustered missense variants and a shared
    transcriptome signature, plus later independent cases, fetuses with the
    recurrent p.Arg330Cys allele, and a mouse model.
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP."
    explanation: Original gene-disease report.
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature."
    explanation: Sizes the reported cohort as of 2026.
  variants:
  - name: p.Arg330Cys
    description: >-
      NM_024528.4:c.988C>T, p.Arg330Cys. Reported in the original cohort and in two
      fetuses with congenital heart defects; in transfected HEK293T cells it lowers
      NKAP transcript but not protein, alters intranuclear distribution and reduces
      HDAC3 binding. Proposed for reclassification as likely pathogenic. All four
      individuals with a p.Arg330 variant reported to 2024 had a cardiac defect.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD."
      explanation: Identifies the allele in two fetuses.
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD."
      explanation: Functional evidence behind the likely-pathogenic call.
  - name: p.Arg204Ser
    description: >-
      ENST00000371410.5:c.612A>C, p.Arg204Ser in exon 4, outside the exon 8-9
      cluster, found by whole-genome sequencing in a 12-year-old with the full
      Marfanoid-intellectual disability picture. Classified as a variant of
      uncertain significance; its pathogenicity requires further analysis.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    evidence:
    - reference: PMID:41917976
      reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pathogenicity of the nucleotide variant of exon 4 of NKAP requires further analysis."
      explanation: The authors' own classification of the variant.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    Diagnosis rests on identifying a hemizygous NKAP missense variant, in
    practice by trio exome or whole-genome sequencing, in a male with intellectual
    disability and a Marfanoid habitus. The clinical picture overlaps the
    broadly defined Lujan-Fryns phenotype, and an NKAP variant was found in one
    of 28 males with that tentative diagnosis.
  diagnosis_term:
    preferred_term: trio exome or genome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present a further familial case of Hackmann-Di Donato syndrome involving an inherited pathogenic NKAP variant, identified through trio exome sequencing."
    explanation: Trio exome sequencing as the diagnostic route.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, the case illustrates the need to test male patients with a Marfanoid phenotype and intellectual disability for mutations in NKAP."
    explanation: States the clinical indication for NKAP testing.
  - reference: PMID:26358559
    reference_title: "Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each."
    explanation: Places NKAP in the differential of the Lujan-Fryns phenotype before the syndrome was delineated.
treatments:
- name: Genetic counselling
  description: >-
    X-linked recessive counselling for the family, including carrier testing of
    the mother and at-risk female relatives; familial transmission is documented.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42481913
    reference_title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these cases, evidence of familial transmission has been documented in five individuals from three unrelated families."
    explanation: Documented inherited cases are the basis for counselling and carrier testing.
- name: Multidisciplinary supportive care
  description: >-
    No disease-specific therapy exists. Management is supportive and follows the
    case-level surveillance plan given to one reported proband: regular
    cardiology follow-up with annual echocardiography for mitral valve prolapse
    and aortic root diameter, orthopaedic care with physical therapy for
    scoliosis, joint hypermobility and recurrent dislocation, neurological
    follow-up with EEG where epilepsy is present (the proband's absence
    epilepsy was treated with ethosuximide), ophthalmological examination, and
    neuropsychological assessment with ongoing educational support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular cardiology follow-up with annual echocardiograms to monitor the mitral valve prolapse and aortic root diameter."
    explanation: Cardiac surveillance element of the single-proband plan.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic care for scoliosis, joint hypermobility, and habitual dislocation, including physical therapy."
    explanation: Orthopaedic element of the single-proband plan.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continued neurology management with routine electroencephalography (EEG) monitoring to manage his absence epilepsy."
    explanation: Neurological element of the single-proband plan.
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropsychological assessment and ongoing educational support owing to his borderline intellectual functioning."
    explanation: Developmental element of the single-proband plan.
  notes: >-
    No management study or guideline exists for this syndrome; the only
    published management is the surveillance plan recorded for one proband,
    quoted above.
- name: Ethosuximide for absence epilepsy
  description: >-
    In the one proband with absence epilepsy, seizures were treated with
    valproic acid and ethosuximide from age 5, valproate was withdrawn at 6, and
    remission has been maintained on ethosuximide since age 11. Single-case
    management of a feature not confirmed as part of the syndrome.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ethosuximide
      term:
        id: CHEBI:4887
        label: ethosuximide
  target_phenotypes:
  - preferred_term: Absence seizures
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:41917976
    reference_title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remission has been maintained since the age of 11 years, and the patient is currently receiving 1000 mg/day of ethosuximide."
    explanation: Single-case treatment and outcome.
animal_models:
- name: nkap C-terminal truncation zebrafish
  species: Zebrafish
  genotype: nkap mutant with C-terminally truncated NKAP
  publication: PMID:31587868
  description: Zebrafish carrying a C-terminally truncated nkap allele show severe developmental defects.
  evidence:
  - reference: PMID:31587868
    reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects."
    explanation: Establishes the model and its developmental phenotype.
  modeled_mechanisms:
  - target: NKAP C-terminal Missense Variant
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: Removes the C-terminal region in which the human missense variants cluster and produces developmental defects; it perturbs the region rather than reproducing a missense lesion.
    limitations: >-
      The allele is a truncation removing the C-terminal region, not a missense
      change within it, so it may behave as a null where the human alleles retain
      protein; the developmental phenotype is not resolved into the human
      neurodevelopmental or skeletal features.
    evidence:
    - reference: PMID:31587868
      reference_title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects."
      explanation: The authors use the model to support the C-terminal region's developmental role, which is the node it is linked to.
- name: Nkap mutant mouse (hemizygous males)
  species: Mouse
  genotype: Nkap c.5_127del (p.Ala2_Gly43del), in-frame 123 bp deletion in exon 1 (N-terminal RS domain), hemizygous males
  publication: PMID:41828556
  description: >-
    CRISPR/Cas9-generated in-frame deletion in the N-terminal RS domain, not the
    C-terminal region mutated in humans. Hemizygous males show altered gait on
    CatWalk analysis, read by the authors as consistent with the hypotonia of
    affected humans, but normal weight and size and normal bone length and
    structure on X-ray, so the Marfanoid skeletal phenotype is not reproduced.
    Embryonic fibroblasts from mutant embryos proliferate poorly and senesce,
    and heterozygous females show skewed X-inactivation against the mutant
    allele.
  evidence:
  - reference: PMID:41828556
    reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
    explanation: Establishes the model and its motor phenotype.
  modeled_mechanisms:
  - target: Impaired Neurodevelopment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Gait alteration is the only neurological readout and is interpreted as a hypotonia correlate.
    limitations: >-
      Gait parameters are an indirect proxy for hypotonia; cognition was not
      assessed, and the engineered allele is described as deleterious rather
      than matching a patient missense variant.
    evidence:
    - reference: PMID:41828556
      reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
      explanation: The authors read the gait change as a hypotonia correlate; that it reflects a neurodevelopmental defect is their inference and ours.
    readouts:
    - name: CatWalk XT gait parameters
      target: Impaired Neurodevelopment
      direction: ALTERED
      interpretation: Motor correlate of the hypotonia seen in affected males.
      evidence:
      - reference: PMID:41828556
        reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Gait analysis studies conducted in male mice hemizygous for mutant NKAP by the CatWalk XT system revealed significant alterations in gait parameters, consistent with hypotonia reported in human mutant NKAP patients."
        explanation: Reports the gait measurement.
  - target: Reduced Cellular Proliferation and Senescence
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: Embryonic fibroblasts from this model are the source of the proliferation and senescence observation.
    limitations: >-
      The allele is an N-terminal in-frame deletion, so the result shows what a
      deleterious Nkap allele does to mouse cells, not what the human C-terminal
      missense alleles do; fidelity to the human disease is unknown.
    evidence:
    - reference: PMID:41828556
      reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Murine embryonic fibroblasts (MEFs) derived from a hemizygous mutant NKAP embryo exhibited markedly reduced proliferation rate and increased senescence compared to WT NKAP MEFs"
      explanation: The measurement made in cells derived from this model.
  - target: Skewed X-Inactivation in Heterozygous Females
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Heterozygous females reproduce the skewed X-inactivation documented in a human NKAP carrier.
    evidence:
    - reference: PMID:41828556
      reference_title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "XCI pattern analysis using methylation-sensitive restriction enzymes demonstrated that mutant NKAP/HA females exhibited significant XCI skewing of the X chromosome bearing the mutant NKAP copy."
      explanation: The skewing is measured directly in the model.
experimental_models:
- name: HEK293T cells expressing NKAP p.Arg330Cys
  experimental_model_type: CELL_LINE
  publication: PMID:38647244
  description: Transient expression of the recurrent patient allele in HEK293T cells.
  evidence:
  - reference: PMID:38647244
    reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level."
    explanation: Establishes the transfection system and its first readout.
  modeled_mechanisms:
  - target: Loss of NKAP-HDAC3 Corepressor Complex Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Shows reduced HDAC3 binding and altered intranuclear distribution of the mutant protein.
    limitations: Overexpression in a non-neural, non-cardiac cell line; endogenous dosage and cell-type context are not modelled.
    evidence:
    - reference: PMID:38647244
      reference_title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3."
      explanation: The measurements made in this system.
discussions:
- discussion_id: nkap_missense_r_loop_genome_instability
  kind: KNOWLEDGE_GAP
  prompt: >-
    NKAP depletion causes R-loop accumulation, DNA damage and replication stress
    in cell lines through loss of the NKAP-HDAC3 complex. Do the hemizygous
    C-terminal missense alleles, which retain protein but lose HDAC3 binding,
    produce the same R-loop phenotype in patient cells?
  rationale: >-
    The patient transcriptome signature (downregulated long, exon-rich genes)
    is also what transcription-coupled R-loop stress would be expected to
    produce, and mutant embryonic fibroblasts proliferate poorly and senesce.
    Resolving this would decide whether the disorder is one of transcriptional
    corepression, of splicing, or of genome maintenance.
  attaches_to:
  - pathophysiology#Loss of NKAP-HDAC3 Corepressor Complex Function
  - pathophysiology#Reduced Cellular Proliferation and Senescence
  evidence:
  - reference: PMID:37322264
    reference_title: "NKAP acts with HDAC3 to prevent R-loop associated genome instability."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "In addition, NKAP prevents R-loop formation by maintaining RNA polymerase II pausing."
    explanation: The depletion result that raises the question; it was obtained without patient alleles.
- discussion_id: nkap_animal_alleles_vs_human_missense
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Both animal models carry alleles that truncate or disrupt Nkap (a C-terminal
    truncation in zebrafish; an N-terminal in-frame deletion in the mouse),
    whereas the human disease is caused by C-terminal missense variants that
    leave protein level unchanged. Do the model phenotypes reflect loss of the C-terminal
    interactions, or a null state the human alleles do not reach?
  rationale: >-
    Complete NKAP loss is lethal in mouse haematopoiesis and T cell development,
    which affected humans do not show, so the human alleles are at most
    hypomorphic for those functions. A knock-in of a patient allele would
    separate the two.
  attaches_to:
  - animal_models#nkap C-terminal truncation zebrafish
  - animal_models#Nkap mutant mouse (hemizygous males)
  evidence:
  - reference: PMID:20610818
    reference_title: "Adult hematopoietic stem cells require NKAP for maintenance and survival."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival."
    explanation: Complete loss is lethal to haematopoiesis in mice, which affected humans do not show, so the human alleles cannot be nulls for this function.
references:
- reference: PMID:31587868
  title: "Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment."
- reference: PMID:42481913
  title: "Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities."
- reference: PMID:41917976
  title: "Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report."
- reference: PMID:41828556
  title: "Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females."
- reference: PMID:38647244
  title: "From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease."
- reference: PMID:37322264
  title: "NKAP acts with HDAC3 to prevent R-loop associated genome instability."
- reference: PMID:36929417
  title: "Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins."
- reference: PMID:26358559
  title: "Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?"
- reference: PMID:19409814
  title: "NKAP is a transcriptional repressor of notch signaling and is required for T cell development."
- reference: PMID:24583034
  title: "The Notch co-repressor protein NKAP is highly expressed in adult mouse subventricular zone neural progenitor cells."
- reference: PMID:30705154
  title: "A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation."
- reference: PMID:20610818
  title: "Adult hematopoietic stem cells require NKAP for maintenance and survival."
📚

References & Deep Research

References

12
PMID:31587868
Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment.
No top-level findings curated for this source.
PMID:42481913
Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain Abnormalities.
No top-level findings curated for this source.
PMID:41917976
Marfanoid phenotype with intellectual disability associated with NKAP mutation: a case report.
No top-level findings curated for this source.
PMID:41828556
Deleterious NKAP Mutations Are Associated with Musculoskeletal Abnormalities in Hemizygous Males and Skewed X Chromosome Inactivation in Heterozygous Females.
No top-level findings curated for this source.
PMID:38647244
From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease.
No top-level findings curated for this source.
PMID:37322264
NKAP acts with HDAC3 to prevent R-loop associated genome instability.
No top-level findings curated for this source.
PMID:36929417
Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins.
No top-level findings curated for this source.
PMID:26358559
Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?
No top-level findings curated for this source.
PMID:19409814
NKAP is a transcriptional repressor of notch signaling and is required for T cell development.
No top-level findings curated for this source.
PMID:24583034
The Notch co-repressor protein NKAP is highly expressed in adult mouse subventricular zone neural progenitor cells.
No top-level findings curated for this source.
PMID:30705154
A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation.
No top-level findings curated for this source.
PMID:20610818
Adult hematopoietic stem cells require NKAP for maintenance and survival.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Hackmann-Di_Donato_Syndrome · 2026-10-15T17:26:47Z · View source

De novo curation of Hackmann-Di Donato syndrome (NKAP, MONDO:0026733) from the stub queue, claim issue #14370. Deep research: falcon (Edison) was requested and failed three times with '503 Failed to authenticate' (providers --check reported falcon UNREACHABLE). Both dr_fallback='--fallback' and '--fallback-provider claude_code' were tried and did not hand over, because deep-research-client classes that 503 as a transient server error rather than a credential failure, so no fallback record was written. claude_code was therefore run directly (just research-disorder claude_code), which is a hand substitution; the report is research/Hackmann-Di_Donato_Syndrome-deep-research-claude_code.md (20/20 references resolved, 3/3 quotes valid, 0 off topic, 64/64 terms resolved; needs_review was set only for a cosmetic NCIT label mismatch). just preflight-dr returned WARN on HDAC3 (18 mentions vs 47 for NKAP); read and judged benign, since HDAC3 is NKAP's corepressor partner and OMIM 300766 is the NKAP gene record. The report's 18 PMIDs were the same set found by an independent PubMed sweep; the seven not cited (T cell, iNKT, HSC, kinetochore and NF-kB papers) are mouse immune biology with no human counterpart in this disease, except PMID:20610818, cited once in the HUMAN_MODEL_MISMATCH discussion. GeneReviews: just check-genereviews --online with synonyms in place reports NO_CHAPTER for GeneReviews and StatPearls. No ClinGen (CGGV) or Orphanet (ORPHA) record for NKAP is cached, so gene_disease_validity is absent. Content: eight-node pathograph (C-terminal missense variant -> loss of NKAP-HDAC3 corepressor function / perturbed spliceosomal exon-ligation association / reduced proliferation and senescence -> transcriptional dysregulation of long exon-rich genes -> cardiac morphogenesis gene dysregulation, impaired neurodevelopment, abnormal skeletal and connective tissue development; skewed XCI in heterozygous females), 20 phenotypes with frequencies from the Fiordaliso 2019 cohort (n=10) as tabulated in PMID:41917976 Table 2, X-linked recessive inheritance with the mouse XCI-skewing evidence, a CASES_IN_LITERATURE prevalence record, NKAP genetic record with p.Arg330Cys (likely pathogenic) and p.Arg204Ser (VUS) variants, diagnosis by exome/genome sequencing with the Lujan-Fryns differential, two supportive treatments, zebrafish and mouse animal models and the HEK293T experimental model with modeled_mechanisms, and two discussions (KNOWLEDGE_GAP on R-loops; HUMAN_MODEL_MISMATCH on truncating vs missense alleles). Craniofacial features whose only abstract-level source is the phrase 'dysmorphic features' are graded directness INDIRECT with the cohort count in the description. Five craniofacial phenotypes and the single-case absence seizures are left without a causal edge on purpose. Validation: just validate, validate-terms (passed; new rows in cache/mondo, cache/hgnc and the diseaseterm enum cache), count-verified-snippets 68/68, check-entity-refs, check-causal-targets, check-coarse-phenotypes (HP:0001627 carries VARIABLE_SPECTRUM), check-enum-values, check-duplicate-keys, check-block-scalar-comments, check-snippet-length (one 3-word snippet lengthened), check-title-snippets, check-snippet-grading, check-retired-support-prose, check-reference-titles, check-folded-hyphens, check-term-cache-integrity all OK; compliance 91.6%. The final batched just validate-disorders run is recorded in the PR body. Pre-PR red-team review (fresh-context subagent following the dismech-pr-review skill) raised five important findings, all taken: the variant-to-proliferation edge was downgraded to INDIRECT_UNKNOWN_INTERMEDIATES because the mouse allele is an N-terminal in-frame deletion (c.5_127del) rather than a C-terminal missense change, and the mouse model now links to that node directly with the allele named in its genotype; the cardiac morphogenesis node was re-parented under the NKAP-HDAC3 node, which is the route PMID:38647244 asserts; the standalone mitral valve prolapse phenotype, whose only abstract-level snippet did not name it, was folded into the congenital heart defect description; the supportive-care treatment now records the case-level surveillance plan in the full text of PMID:41917976 instead of claiming no management literature exists; and repository-state and process prose was removed from notes. Also taken: Midface retrusion added (7/10, same footing as the other craniofacial rows), the human haemophilia-A carrier sentence added as BACKGROUND evidence on the inheritance block and the X-inactivation node, quote_role BACKGROUND on the exon 8-9 sentence, the co-IP/ChIP quote regraded IN_VITRO, the zebrafish link changed to PERTURBS, and wording fixes (eight families; reported rather than recurrent alleles; the p.Arg330 cardiac correlation qualified to the four cases reported to 2024). Not taken: a FAILS_TO_RECAPITULATE link from the mouse to the skeletal node, because the normal-skeleton observation is full-text only and that link requires quotable evidence; it is stated in the model description instead. After the round: 71/71 snippets verified, 13 of 20 phenotypes causally wired, compliance 92.3%. Six references fetched for the research report but not cited by the entry were left uncommitted. CI round: the gene-activity-grounding gate flagged NKAP as wired into the pathograph with no molecular function on its node; transcription corepressor activity and histone deacetylase binding (DECREASED) were bound on the variant node. PR review round 1 (ai4c-reviewer, CHANGES_REQUESTED). The reviewer's premise, that full-text quotes from the cached PMID:41917976 pass validation, was tested against the exact CI gate (`just validate-disorders`, which passes --no-full-text) with a comparison-table row as a snippet, and it verified, so the earlier assumption that only abstract sentences are quotable was wrong. All four important items taken: Cryptorchidism and Hypospadias rows added (2/10 each, with the 5/10 any-genital-anomaly row), and the notes sentence that had claimed no abstract states them removed, along with the unsourced central-obesity claim; every frequency-bearing phenotype row now quotes its comparison-table row directly (DIRECT) instead of the 'dysmorphic features' abstract sentence graded INDIRECT; Midface retrusion kept on HP:0011800 with the paper's 'hypoplasia of the midsection' sentence quoted and the description saying the table words it as the bottom half of the face; supportive care now carries the four surveillance sentences of the single-proband plan as evidence, with the note rewritten. Suggestions taken: Mitral valve prolapse restored as its own row (3/10 plus the proband), Ventricular septal defect (both fetuses) and Increased nuchal translucency rows from the full text of PMID:38647244, with the VSD row wired from the cardiac morphogenesis node on the authors' own model statement, and an ethosuximide single-case treatment row (CHEBI:4887) targeting the absence-seizure phenotype. The tetralogy-of-Fallot-like presentation is described on the VSD row rather than bound, because the source states it only as a possibility. After the round: 94/94 snippets and 106 titles verified by validate-disorders, 25 phenotypes with 14 causally wired, compliance 93.6%.

Claude Code ▸
Hackmann-Di Donato Syndrome (NKAP-related X-linked syndromic intellectual disability): Research Report
claude-haiku-5-5, claude-opus-5-5 6 citations 2026-10-15T13:14:55.741591

Hackmann-Di Donato Syndrome (NKAP-related X-linked syndromic intellectual disability): Research Report

Prepared: 2026-10-15 · Target: MONDO:0026733 · Category: Mendelian

Sources and how far to trust them. Most of this report rests on the 18 references already cached in this worktree's references_cache/. Quotes from those are marked (abstract) or (full text) and can be copied as snippets. I also used two web sources: - the PMC full text of Fiordaliso et al. 2019 (PMC6848994), which supplies the per-feature counts; - the NCBI MedGen record (C5393302).

The per-feature counts came through a WebFetch summary, not a cached file. Check every number and quote taken from that source against the PDF before using it as a snippet.

Ontology CURIEs below come from MedGen, the stub, or the draft entry, or are leads I wrote from memory. Marked ⚠ means not yet looked up. Per the repository's term contract, run runoak or just validate-terms on each before binding.

1. Disease Information

Overview. Hackmann-Di Donato syndrome (HDDS; OMIM-style symbol MRXSHD) is an X-linked recessive neurodevelopmental disorder. It is caused by hemizygous missense variants in NKAP (Xq24), which encodes the NF-κB activating protein. NKAP is a nuclear-speckle and spliceosome-associated protein that also acts as a transcriptional corepressor with HDAC3.

The defining publication is Fiordaliso et al. 2019 (PMID:31587868, Am J Hum Genet). It reported 10 affected males from 8 families with: - developmental delay or intellectual disability; - hypotonia; - Marfanoid habitus with tall stature; - joint laxity, arachnodactyly and scoliosis; - behavioral abnormalities; - a recognizable long-face gestalt.

"we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins." — PMID:31587868 (abstract)

"The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis." — PMID:31587868 (abstract)

Eponym. The syndrome is named after Karl Hackmann and Nataliya Di Donato. Their 2016 re-examination of patients clinically diagnosed with Lujan-Fryns syndrome found an NKAP variant in one individual:

"X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each." — PMID:26358559 (abstract)

Identifiers

System ID Source
MONDO MONDO:0026733 "intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type" stub, MedGen
OMIM (phenotype) 301039 MedGen; PMID:38647244 ("MRXSHD, MIM: #301039")
OMIM (gene) 300766 (NKAP) MedGen
MedGen C5393302 MedGen
NCBI Gene 79576 (NKAP) MedGen
HGNC hgnc:29873 (NKAP) stub, draft
Orphanet Not found. No Orphanet record turned up in search; do not cite an ORPHA code until one is located. —
ICD-10/ICD-11, MeSH No disease-specific code found. Parent concepts only (X-linked ID). —
MONDO parent MONDO:0020119 "X-linked syndromic intellectual disability" stub

Synonyms - Hackmann-Di Donato syndrome; also spelled Hackman-Di Donato (PMID:41917976 uses the single-n form) - Intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type (MRXSHD) - Mental retardation, X-linked, with Marfanoid habitus, 2 (MedGen) - NKAP-related syndrome / NKAP mutation-related disorder (PMID:36929417, PMID:38647244)

Data provenance. Everything here comes from published case series and case reports (aggregated, disease-level). No EHR or registry data exist.

Reported individuals to date (about 14): - 10 males in Fiordaliso 2019; - 2 male fetuses in Xu 2024 (PMID:38647244); - 1 boy with an exon-4 variant of uncertain significance in Semyachkina 2026 (PMID:41917976); - 1 or more members of a family in Gérard 2026 (PMID:42481913), including "the oldest known patient".

Gérard 2026 states: "Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature."

2. Etiology

Primary cause. Germline hemizygous missense variants in NKAP. Every variant classified pathogenic or likely pathogenic falls in exons 8–9, which encode the C-terminal (DUF926) region.

"All pathogenic nucleotide variants were located in exons 8 and 9, encoding the C-terminal part of NKAP." — PMID:41917976 (full text)

Genetic risk factors - Variant hotspots at p.Arg330 and p.Arg333 (see §4). - Unaffected or mildly affected carrier mothers. Three affected males in Fiordaliso 2019 inherited the variant from such mothers. Xu 2024 found carrier grandmothers and aunts in a multigenerational family. - Maternal germline mosaicism in one sibship. Two brothers carried an apparently de novo variant (PMID:41917976 full text: "In one pedigree, two siblings appeared to have inherited the mutation due to maternal germline mosaicism."). - Modifier genes: none identified.

Environmental risk factors. None reported. In Xu 2024 the mother of the CHD fetuses reported "no history of illness, medication usage or exposure to either radiation or harmful substances during her pregnancy" (PMID:38647244 full text).

Protective factors and gene–environment interactions. None reported.

Sex-specific protection in females. The plausible explanation is skewed X-inactivation, but it is only partly demonstrated: - Mouse: heterozygous females with a deleterious Nkap allele showed 83–97% inactivation of the mutant X, explained as secondary selection against cells expressing the mutant allele (PMID:41828556). - Human: one report of a nonsense NKAP variant in a hemophilia A carrier with extreme skewing. It is cited as ref. 10 in PMID:41828556, but its PMID is not cached; fetch it before citing. - Not measured in HDDS carrier mothers. Fiordaliso 2019 reports none: "Mothers carrying NKAP mutations were unaffected or much less severely affected." This is a curatable knowledge gap.

3. Phenotypes

Frequencies are from Fiordaliso 2019 Table 1 (n=10 males, ages 4–21 years). Verify them against the PDF before encoding. Suggested HPO terms come from MedGen's HPO list where available; ⚠ marks a term to look up.

Core neurodevelopmental features

Phenotype Freq. HPO (suggested) Notes
Global developmental delay / intellectual disability 10/10 HP:0001263 Global developmental delay; HP:0001249 Intellectual disability Onset in infancy. Speech delay is prominent and walking is mildly delayed (OMIM/MedGen summary). Severity ranges from borderline intelligence (PMID:41917976) to ID.
Hypotonia 10/10 HP:0001252 Hypotonia (MedGen lists "Hypotonia") Congenital/infantile. A mouse correlate exists: reduced grip strength (PMID:41828556).
Behavioral abnormality (ADHD and/or aggression) 5/10 HP:0007018 ADHD ⚠; HP:0000718 Aggressive behavior ⚠ Childhood onset.
Delayed speech common (OMIM summary) HP:0000750 Delayed speech and language development ⚠
Seizures (absence epilepsy) 1 case (VUS case) HP:0002121 Absence seizure ⚠ PMID:41917976 only. The genotype is a VUS, so do not generalize.
White matter lesions on MRI (stable) 1 family HP:0002500 Abnormality of the cerebral white matter ⚠ PMID:42481913: "Brain MRI revealed stable white matter lesions." Not systematically assessed in other cases.

Growth and habitus

Phenotype Freq. HPO Notes
Tall stature / Marfanoid habitus 10/10 HP:0001519 Disproportionate tall stature (MedGen); HP:0001166 Arachnodactyly The draft entry uses HP:0001519 with preferred_term "Marfanoid habitus", which matches MedGen.
Central/abdominal obesity 5/10 HP:0012743 Abdominal obesity ⚠ (MedGen lists the label)

Musculoskeletal

Phenotype Freq. HPO
Joint laxity/hypermobility 9/10 HP:0001382 Joint hypermobility ⚠
Arachnodactyly 8/10 HP:0001166 ⚠
Scoliosis 6/10 HP:0002650 ⚠
Pectus carinatum or excavatum 5/10 HP:0000768 / HP:0000767 ⚠
Camptodactyly 4/10 HP:0012385 ⚠
Joint contractures stated in the abstract; no separate count HP:0001371 Flexion contracture ⚠
Talipes equinovarus 1/10 HP:0001762 ⚠
Recurrent shoulder dislocation, dolichostenomelia, pes planovalgus VUS case PMID:41917976

Craniofacial

Phenotype Freq. HPO
Long face 8/10 HP:0000276 ⚠
Prominent/protruding ears 8/10 HP:0000411 ⚠
Open mouth appearance 7/10 HP:0000194 ⚠
Midface retrusion 7/10 HP:0011800 ⚠
Short philtrum 7/10 HP:0000322 ⚠

Cardiovascular

Fiordaliso 2019 reports roughly 6/10 with a cardiac finding. Xu 2024 counts 8/12 across all reported cases, including the two fetuses (PMID:38647244 Table 3).

Phenotype Freq. HPO
Mitral regurgitation / mitral valve prolapse 3/10 HP:0001653 ⚠; HP:0001634 ⚠
Atrial septal defect 1/10 HP:0001631 ⚠
Ventricular septal defect 1/10 postnatal; 2/2 fetuses HP:0001629 ⚠
Patent ductus arteriosus 1/10 postnatal + 1 fetus HP:0001643 ⚠
Aortic root dilatation 1/10 HP:0002616 Aortic root aneurysm (MedGen) ⚠
Pulmonary stenosis, overriding aorta (tetralogy of Fallot-like) 1 fetus HP:0001642 ⚠; HP:0002623 ⚠

Genotype–phenotype note:

"Particularly, all four individuals carrying mutation at p.R330 had cardiac defects, strongly suggesting a correlation between NKAP p.R330 mutation and cardiac development." — PMID:38647244 (full text)

Genitourinary

Phenotype Freq. HPO
Cryptorchidism 4/10 HP:0000028 ⚠

Prenatal findings (PMID:38647244)

  • Increased nuchal translucency of 3.0 mm at 12 weeks (HP:0010880 ⚠).
  • Mild lateral ventriculomegaly.
  • Choroid plexus cysts (HP:0002190 ⚠).
  • Fetal tachycardia.

"These prenatal anomalies include cardiac defect and thickened NT, which could be observed as early as 12 weeks gestation" — PMID:38647244 (full text)

Phenotype the draft entry includes but the sources do not support

Macrocephaly is in the draft YAML description. It does not appear in Fiordaliso 2019 (per the full-text read), MedGen's HPO list, or any cached reference. Remove it from the description unless a source turns up.

Quality of life

No QoL instrument data exist (no EQ-5D, SF-36 or PROMIS). The main inferred burden is lifelong ID with behavioral problems, connective-tissue complications (scoliosis, joint instability), and cardiac follow-up.

4. Genetic / Molecular Information

Causal gene: NKAP (hgnc:29873; NCBI Gene 79576; OMIM 300766; Xq24). The transcript is NM_024528.4, encoding a 415-amino-acid protein of about 47 kDa. Its domains are: - an N-terminal RS (arginine/serine-rich) domain that mediates nuclear localization; - a central basic region; - a C-terminal DUF926 domain that binds HDAC3 and spliceosomal proteins. Shapiro 2019 (PMID:30804042) places the minimal HDAC3-binding site around F347/Y352.

Variants reported

Variant (NM_024528.4) Protein Families / individuals Origin Classification Source
c.988C>T p.Arg330Cys 1 male (de novo) + 2 fetuses (maternal) de novo; maternal Likely pathogenic (PS2+PM2_Sup+PM5_Sup+PP1_Sup per Xu); ClinVar VCV 827654 listed as VUS at the time PMID:31587868; PMID:38647244
c.989G>A p.Arg330His 1 male de novo LP PMID:31587868
c.998G>A p.Arg333Gln 6 males / 4 families (recurrent hotspot) maternal; germline mosaic sibs; unknown P/LP PMID:31587868
c.1010T>C p.Ile337Thr 1 male de novo LP PMID:31587868
c.1082G>A p.Arg361Gln 1 male unknown LP PMID:31587868
c.612A>C p.Arg204Ser (exon 4) 1 boy not stated in abstract VUS PMID:41917976
familial inherited variant (not stated in abstract) — 1 family maternal pathogenic PMID:42481913

Xu 2024 Table 3 prints c.988G>A for p.R333Q in some rows. Fiordaliso's own text gives c.998G>A, which is the correct HGVS. Use c.998G>A.

  • Variant type: all are missense. No truncating, splice or copy-number variant has been reported in an affected male. This is consistent with complete loss of NKAP being lethal (see the model data below).
  • Population frequency: the hotspot alleles are absent from gnomAD (PM2 cited in PMID:38647244).
  • Origin: germline. There is no somatic role in HDDS. Somatic NKAP loss in sarcoma (PMID:27694884) is a separate cancer-biology observation and not part of this disease.

Functional consequence. This is best described as partial or altered loss of function confined to the C-terminal interaction domain, not null: - NKAP mRNA and protein levels were normal in patient lymphoblastoid cell lines (LCLs), and HDAC3 levels and distribution were unchanged (Fiordaliso, full text). - p.R330C reduced NKAP–HDAC3 co-IP from 44.9% to 16.7% and shifted NKAP to the nuclear periphery in HEK293T/HeLa overexpression experiments (PMID:38647244). - In mice, complete Nkap deletion in hematopoietic cells is lethal (PMID:20610818). In zebrafish, a C-terminal truncation is lethal by 4 dpf (PMID:31587868).

Suggested functional_impact_category: PARTIAL_LOSS_OF_FUNCTION, or leave it unset with a note. Dominant-negative and gain-of-function have not been tested; do not assert either.

Genotype–phenotype. p.Arg330 variants are associated with congenital heart disease (4/4 carriers). No other correlation is established.

Epigenetics. No disease-specific methylation signature (episignature) has been reported. Skewed X-inactivation in carrier females has been shown only in the mouse (PMID:41828556).

Chromosomal abnormalities. None. This is a point-mutation disorder, and karyotype and chromosomal microarray were normal in the fetal proband (PMID:38647244).

ClinGen. No gene–disease validity curation for NKAP–HDDS was found. Leave gene_disease_validity absent.

5. Environmental Information

There are no environmental, lifestyle or infectious contributors. The environmental: section should stay empty.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Germline hemizygous missense variant in the NKAP C-terminal (DUF926) domain (exons 8–9; hotspots R330, R333). Demonstrated in patients (PMID:31587868).
  2. The variant alters NKAP protein interactions without lowering NKAP abundance.
  3. Patient LCLs: NKAP mRNA and protein are normal (PMID:31587868 full text).
  4. 2a. Reduced NKAP–HDAC3 association. Demonstrated in vitro for p.R330C only (PMID:38647244). Inferred for other variants, which sit in the HDAC3-binding region. The importance of this interaction is supported by the Y352A HDAC3-binding-null mouse (PMID:30804042, PMID:31387873).
  5. 2b. Possible perturbation of NKAP's role in the post-catalytic spliceosome (C*/P complex, exon ligation). Inferred from the structural location of the variants (PMID:30705154: "CACTIN, SDE2, and NKAP-factors implicated in alternative splicing-further stabilize the catalytic conformation of the spliceosome during exon ligation").
  6. 2c. Altered intranuclear (nuclear speckle) distribution. In vitro, p.R330C only (PMID:38647244). The nuclear-speckle framing is from the review PMID:36929417.
  7. Transcriptional dysregulation. Loss of NKAP–HDAC3 corepressor activity, including on Notch targets, leads to a distinctive transcriptome signature.
  8. Patient LCLs show 455 upregulated and 721 downregulated genes, with HES1 and JAG1 up (PMID:31587868 full text).
  9. 3a. Long genes with many exons are selectively downregulated. Demonstrated in patient LCLs (PMID:31587868 abstract: "transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers").
  10. 3b. Notch target genes are de-repressed. Demonstrated in mouse T cells (PMID:19409814: Hes1, Deltex1 8–20-fold higher with NKAP loss). Patient LCLs show HES1/JAG1 changes. That this occurs in neural or mesenchymal tissue is inferred.
  11. Splicing changes in patient cells were modest: only 39 events, with some increase in intron retention. This is weak evidence that mis-splicing is the main driver.
  12. Branching tissue consequences (all inferred; none shown in human tissue):
  13. 4a. Brain: disrupted neurodevelopmental gene programs lead to ID/DD, hypotonia and behavioral abnormality. Supporting context: NKAP is highly expressed in neural progenitors and migrating neuroblasts (mouse SVZ/RMS, PMID:24583034), and long, exon-rich genes are enriched among neuronal and synaptic genes. That second point is my inference, not a statement from the cited sources.
  14. 4b. Connective tissue / skeleton: dysregulated extracellular-matrix gene expression (ECM terms enriched in the LCL differentially expressed genes) leads to Marfanoid habitus, joint laxity, arachnodactyly and scoliosis. Inferred; the mechanism is unknown.
  15. 4c. Heart: altered expression of cardiac morphogenesis genes (JAG1 and DNAH11 up, DHRS3 down with p.R330C in HEK293T) leads to septal defects, outflow-tract and valve anomalies (PMID:38647244). In vitro inference. The authors themselves note that the direction of change for DHRS3 conflicts with the LCL data.
  16. Clinical syndrome: ID, hypotonia, Marfanoid habitus, connective-tissue features and variable CHD.

Parallel branch to model as a hypothesis, not a demonstrated disease mechanism

Genome-stability functions of NKAP: - SUMOylated NKAP anchors CENP-E at kinetochores for chromosome alignment (PMID:27694884). - NKAP–HDAC3 prevents R-loop accumulation and DNA damage (PMID:37322264). - Mutant NKAP mouse embryonic fibroblasts proliferate 3.4-fold less, become senescent, and upregulate p27/p57, IL-1β and IL-6 (PMID:41828556).

None of these has been tested with HDDS patient variants. Their relevance to HDDS is a knowledge gap. The SUMOylation sites lie in amino acids 277–415, which overlaps the patient-variant region and makes this a reasonable hypothesis.

NKAP biology by category

  • Molecular pathways:
  • Notch signaling (NKAP is a corepressor with CIR/HDAC3): PMID:19409814, PMID:24583034.
  • NF-κB activation (original description, overexpression in 293 cells): PMID:14550261.
  • Pre-mRNA splicing at exon ligation: PMID:30705154.
  • Cellular processes: transcriptional repression; mitotic chromosome alignment; R-loop suppression and genome stability; hematopoietic stem cell maintenance (PMID:20610818, PMID:30804042); T/iNKT/Treg maturation (PMID:21624937, PMID:23481390, PMID:31387873). The immune and hematopoietic phenotypes are mouse conditional-knockout findings with no reported human HDDS counterpart. Do not add immune phenotypes.
  • Protein dysfunction: altered binding (HDAC3) and altered localization. Not misfolding or aggregation.
  • Metabolic and immune involvement: none reported in patients.
  • Molecular profiling: LCL RNA-seq in Fiordaliso 2019. No GEO accession is quoted in the summary I have; check the paper's data availability statement before running just discover-datasets.

Suggested ontology terms (⚠ verify all)

GO, biological processes - GO:0000122 negative regulation of transcription by RNA polymerase II - GO:0045746 negative regulation of Notch signaling pathway - GO:0000398 mRNA splicing, via spliceosome - GO:0051310 metaphase chromosome alignment - GO:0007399 nervous system development - GO:0007507 heart development - GO:0030198 extracellular matrix organization

GO, cellular components - GO:0016607 nuclear speck - GO:0071013 catalytic step 2 spliceosome - GO:0000776 kinetochore

CL, cell types - CL:0000540 neuron - CL:0011020 neural progenitor cell - CL:0000057 fibroblast - CL:0000746 cardiac muscle cell (for the CHD branch) - CL:0000037 hematopoietic stem cell (model-only context)

Interacting gene: HDAC3 (HGNC ID ⚠ — look it up; do not write it from memory).

7. Anatomical Structures Affected

Primary systems - Central nervous system: brain, UBERON:0000955 ⚠. - Musculoskeletal and connective tissue: vertebral column UBERON:0001130 ⚠ (scoliosis); joints; digits. - Heart: UBERON:0000948 ⚠. Specifically the interventricular and interatrial septa, mitral valve and aortic root.

Secondary systems - Testis / cryptorchidism (urogenital). - Cerebral white matter (one family).

Subcellular: nucleus, nuclear speckles, spliceosome, and kinetochores during mitosis.

Lateralization: systemic and bilateral. Scoliosis is asymmetric by nature.

8. Temporal Development

  • Onset: congenital or prenatal.
  • Cardiac defects and increased nuchal translucency are detectable from 12 weeks' gestation (PMID:38647244).
  • Hypotonia and developmental delay appear in infancy.
  • Course: a static neurodevelopmental disorder, with no regression reported.
  • Skeletal features such as scoliosis and Marfanoid proportions become more evident during childhood growth.
  • The white matter lesions in the Gérard family were "stable".
  • Duration: lifelong.
  • Ages reported: 4–21 years in the original cohort. Gérard 2026 reports the oldest known patient; the exact age is not in the abstract.
  • Stages, remission, critical periods: not defined. Early intervention during infancy and childhood is the main window for developmental therapies (general principle; not disease-specific evidence).

9. Inheritance and Population

  • Inheritance: X-linked recessive. HP:0001419 is used in the draft; the OMIM/MedGen designation agrees.
  • Penetrance in hemizygous males: apparently complete for C-terminal variants, with variable expressivity, especially for cardiac involvement.
  • Heterozygous females:
  • Carrier mothers were "unaffected or much less severely affected".
  • In Xu 2024, female carriers (mother, aunt, grandmother) were healthy.
  • An uncle in that family had developmental delay and spinal instability and died at age 1; he was not genotyped.
  • De novo rate: 6/10 in the original cohort, as stated by Xu 2024 (Fiordaliso reports 4 apparently de novo individuals plus 2 brothers from germline mosaicism).
  • Germline mosaicism: yes, one maternal case.
  • Anticipation, founder effects, consanguinity: none.
  • Epidemiology:
  • Prevalence is unknown.
  • About 14 individuals have been reported worldwide.
  • Populations: European (German, Czech, Italian, UK), US, Japanese, Korean, Chinese (fetuses) and Russian/Slavic.
  • Suggested prevalence record: measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED, citing PMID:42481913 ("Only 12 individuals …").
  • Sex ratio: affected individuals are male.

10. Diagnostics

Genetic testing (the main route) - Exome or genome sequencing, ideally trio, is the diagnostic test. Trio exome was used in PMID:38647244 and PMID:42481913, and genome sequencing in PMID:41917976. - NKAP is on the Genomics England PanelApp intellectual disability panel (PanelApp). - X-exome sequencing first detected it in a Lujan-Fryns-like patient (PMID:26358559). - Chromosomal microarray and karyotype are normal; they are useful only for excluding differentials.

Supporting work-up - Echocardiography for septal, valve and aortic-root disease. - Spine radiographs for scoliosis. - Brain MRI: white matter lesions in one family. Gérard 2026 suggests systematic neuroimaging. - EEG if seizures occur. - Prenatal: nuchal translucency and fetal echocardiography, with prenatal exome sequencing in an at-risk family.

Biomarkers: none validated. The patient-LCL transcriptome signature (downregulated long, exon-rich genes) is research-only.

Clinical criteria: none formalized. Hackmann 2016 argues that "the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS" (PMID:26358559).

Differential diagnosis (all Marfanoid habitus with ID): - Lujan-Fryns syndrome (MED12; also UPF3B, ZDHHC9): nasal speech and specific facies. - Marfan syndrome (FBN1): ectopia lentis and aortic dilatation, with normal intellect. - Loeys-Dietz syndrome. - Homocystinuria: run plasma homocysteine. - Stickler syndrome. - Other nuclear-speckleopathies (ZTTK/SON) (PMID:36929417).

11. Outcome / Prognosis

  • Survival: no data. Postnatal patients have been followed into adulthood (21 years in the original cohort; older in the Gérard family).
  • Pregnancy outcomes: both p.R330C fetuses were terminated after a CHD diagnosis.
  • Morbidity: lifelong intellectual disability; behavioral problems; risk of scoliosis and joint dislocation; cardiac valve and septal disease, plus potential aortic-root dilatation needing surveillance.
  • Prognostic factors: p.Arg330 variants predict CHD (based on 4/4 carriers). Nothing else is known.
  • QoL measures: none published.

12. Treatment

There is no disease-specific or disease-modifying therapy, and no clinical trials. ClinicalTrials.gov and ICTRP searches are not indicated; none was found. Management is supportive and follows standard care for ID and connective-tissue disorders. These recommendations are by analogy; no HDDS-specific guideline exists.

Intervention NCIT (from the CLAUDE.md list; verify) therapeutic_modality
Early developmental, speech and occupational therapy NCIT:C15315 Rehabilitation; NCIT:C15302 Physical Therapy BEHAVIORAL
Behavioral management (ADHD/aggression); stimulant or other pharmacotherapy as indicated NCIT:C15986 Pharmacotherapy (+ therapeutic_agent only if a source names a drug) —
Cardiology surveillance; surgical repair of significant CHD NCIT:C15329 Surgical Procedure SURGERY
Orthopedic management of scoliosis (bracing or spinal fusion) NCIT:C16186 Orthopedic Surgical Procedure SURGERY
Antiseizure medication when epilepsy is present NCIT:C15986 SMALL_MOLECULE
Genetic counseling NCIT:C15240 Genetic Counseling —
Supportive care NCIT:C15747 Supportive Care —

Evidence gap. No cached reference describes treatment outcomes. Any treatment rows will need evidence: cite the case reports' management descriptions, or record each row as a general-care recommendation with a notes: explanation.

13. Prevention

  • Primary prevention: not applicable.
  • Genetic counseling:
  • A carrier mother has a 50% risk of an affected son with each male pregnancy.
  • An apparently de novo case still carries recurrence risk because of possible germline mosaicism, which has been documented.
  • Testing options in a known family: carrier testing of female relatives, prenatal diagnosis (shown in PMID:38647244), and preimplantation genetic testing.
  • Secondary prevention: cardiac and spinal surveillance after diagnosis.
  • Newborn screening: not applicable.

14. Other Species / Natural Disease

  • No naturally occurring animal disease is known, and nothing is listed in OMIA (not searched exhaustively).
  • Orthologs:
  • Mouse Nkap (on the X chromosome).
  • Zebrafish nkap.
  • Rat to human conservation of the C-terminal lysines (PMID:27694884).
  • R330 is "highly conserved among various species" (PMID:38647244).
  • NCBI Gene IDs for the orthologs were not retrieved; look them up before encoding.

15. Model Organisms

Model Genotype Phenotype recapitulation Limitations Source
Zebrafish (Danio rerio, NCBITaxon:7955) nkap c.859delA (exon 8), p.Arg298GlufsTer6, a C-terminal truncation that escapes NMD; also the nkap^hi1477Tg insertion line Homozygotes: eye, intestinal and cardiac edema; notochord curvature; CNS necrosis from 2 dpf; no heartbeat and 100% lethality by 4 dpf. Heterozygotes are normal. Truncation, not a patient missense allele. Too severe and lethal to model ID or habitus. PMID:31587868
Mouse, germline (NCBITaxon:10090) Nkap Δ123bp in-frame N-terminal (RS-domain) deletion, hemizygous males Reduced forelimb grip strength and altered gait (shorter stride, longer duty cycle), consistent with hypotonia. Normal survival to 18 months, normal size, normal bone length on X-ray. Does not recapitulate Marfanoid habitus. The allele is in the N-terminus, not the C-terminal hotspot. Females show skewed XCI. A frameshift allele (Δ70bp) could not be transmitted. PMID:41828556
Mouse, conditional knockouts Mx1-cre / Vav-cre; Lck-cre; CD4-cre; Y352A knock-in (HDAC3-binding-null) Hematopoietic stem cell failure and perinatal lethality; blocked αβ T-cell, iNKT and Treg maturation; lethal autoimmunity with Y352A in Tregs Hematopoietic and immune only, with no human HDDS correlate. Shows that NKAP–HDAC3 binding is essential in vivo. PMID:20610818, PMID:19409814, PMID:21624937, PMID:23481390, PMID:30804042, PMID:31387873
Mouse embryonic fibroblasts Δ123bp 3.4-fold lower proliferation; senescence (SA-β-gal positive; p27/p57, IL-1β, IL-6 up) In vitro, N-terminal allele PMID:41828556
Patient LCLs (human, in vitro) p.R333Q, p.R361Q Transcriptome signature (long-gene downregulation, HES1/JAG1 changes) Non-neural cell type PMID:31587868
HEK293T / HeLa overexpression p.R330C Reduced HDAC3 binding, perinuclear mislocalization, altered JAG1/DNAH11/DHRS3 expression Overexpression system PMID:38647244

Suggested model links (modeled_mechanisms): - Zebrafish → "Dysregulated Transcription": PARTIALLY_RECAPITULATES, fidelity: LOW. - Mouse Δ123bp → the hypotonia phenotype: PARTIALLY_RECAPITULATES, fidelity: LOW. Add a BOUNDARY_OMISSION divergence (no Marfanoid habitus) and a PROXY_QUANTITY divergence (grip strength standing in for hypotonia).

Knowledge gap worth recording (HUMAN_MODEL_MISMATCH): no model carries a patient C-terminal missense allele, and no iPSC-derived neuron or organoid model exists.

Notes for curating kb/disorders/Hackmann-Di_Donato_Syndrome.yaml

  1. File name. The stub's proposed_name is Intellectual_Developmental_Disorder_X-linked_Syndromic_Hackmann-Di_Donato_Type, but the draft uses Hackmann-Di_Donato_Syndrome. Either is fine. Delete stubs/Intellectual_Developmental_Disorder_X-linked_Syndromic_Hackmann-Di_Donato_Type.yaml in the PR.
  2. Remove "macrocephaly" from the draft description; no source supports it. "Joint hypermobility" (9/10 joint laxity) and "scoliosis" are supported.
  3. Build out the pathograph. Add the HDAC3-binding and intranuclear-localization nodes, split "Dysregulated Transcription" into its Notch-target and long-gene branches, and wire edges to the neurodevelopmental, connective-tissue and cardiac phenotypes. Without these the phenotypes stay disconnected (just list-disconnected-phenotypes).
  4. Discussions. Record XCI in carrier mothers and the genome-stability functions as KNOWLEDGE_GAP discussions.
  5. Exon-4 variant. Keep p.Arg204Ser out of the causative variant list or mark it VUS (clinical_significance), citing PMID:41917976.
  6. No GeneReviews chapter is expected. Confirm with just check-genereviews.
  7. Every snippet quoted above from an "(abstract)" or cached "(full text)" source should be checked with just count-verified-snippets. Numbers from the PMC6848994 WebFetch summary are not in the local cache: that file (PMID_31587868.md) is abstract-only, so quote only its abstract.

Sources

Cached references - PMID:31587868 · PMID:26358559 · PMID:38647244 · PMID:41917976 · PMID:42481913 - PMID:41828556 · PMID:36929417 · PMID:30705154 · PMID:19409814 · PMID:20610818 - PMID:21624937 · PMID:23481390 · PMID:30804042 · PMID:31387873 · PMID:27694884 - PMID:37322264 · PMID:24583034 · PMID:14550261

Web sources - Fiordaliso et al. 2019, PMC full text - MedGen C5393302 - Xu et al. 2024, PMC - Genomics England PanelApp – NKAP - CHOP news release, 2019 - ZFIN publication ZDB-PUB-191008-1

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 3
Quoted claims not found in source 0
References weighed for topical relevance 20
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 64
Resolved 64
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • NCIT:C15986 (2 mentions) - the report calls it "Antiseizure medication when epilepsy is present"; NCIT calls it Pharmacotherapy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • NCBITaxon:10090 (1 mention) - the report calls it "Mouse, germline"; NCBITaxon calls it Mus musculus, and lists "mouse" among its other names