Short-Rib Thoracic Dysplasia 6 With or Without Polydactyly (SRTD6) — Comprehensive Research Report

1. Disease Information

Overview. Short-rib thoracic dysplasia 6 with or without polydactyly (SRTD6) is an autosomal recessive skeletal ciliopathy caused by biallelic mutation of the NEK1 gene on chromosome 4q33. It belongs to the short-rib thoracic dysplasia (SRTD) group of disorders — historically also called short rib–polydactyly syndrome (SRPS) — and corresponds specifically to short rib–polydactyly syndrome type II, Majewski type. SRTD6 is a lethal osteochondrodysplasia in its classic (homozygous-null) presentation, characterized by a severely constricted, narrow thoracic cage; short, horizontally oriented ribs; short long bones; and a "trident" (three-pronged) acetabular roof, together with variable polydactyly and multiorgan visceral anomalies (OMIM #263520; DOID:0110092).

Key identifiers: - OMIM: #263520 — SHORT-RIB THORACIC DYSPLASIA 6 WITH OR WITHOUT POLYDACTYLY; SRTD6 (omim.org/entry/263520) - MONDO: MONDO:0009894 - Disease Ontology: DOID:0110092 - ICD-10-CM: Q77.2 (Asphyxiating thoracic dysplasia) - Gene: NEK1 (HGNC), OMIM gene entry 604588, chr4q33 - UMLS/MedGen concept: C0024507 (NCBI GTR)

Synonyms: Majewski syndrome; Short rib-polydactyly syndrome, type II (SRPS2); Short rib-polydactyly syndrome type IIA (SRPS2A); Polydactyly with neonatal chondrodystrophy, type II; Short-rib polydactyly syndrome type Majewski (JAX DOID browser).

Data provenance: Knowledge is derived almost entirely from aggregated disease-level resources (OMIM, GeneReviews-style skeletal-ciliopathy reviews, structured case-report literature and prenatal case series) rather than large EHR cohorts — this is a rare Mendelian disorder without a dedicated national registry, so most quantitative data (mutation counts, cilia measurements) come from individual research cohorts/case series of a few dozen families total (Thiel et al. 2011, PMID:21211617; El Hokayem et al. 2012, PMID:22499340).

2. Etiology

Primary genetic cause. SRTD6 is caused by homozygous or compound heterozygous loss-of-function mutation in NEK1, which encodes a NIMA-related serine/threonine kinase (NEK1) required for cilium assembly, and separately implicated in DNA double-strand-break repair/checkpoint control and neuronal development (OMIM #263520; Thiel et al. 2011). NEK1 has relatively high expression in the growth plate, consistent with the skeletal phenotype.

Founding mutations. In the discovery study (Thiel et al., AJHG 2011, PMID:21211617), homozygosity mapping in two consanguineous families identified: - Family 1: homozygous nonsense mutation c.379C>T (p.Arg127X) - Family 2: homozygous splice-site mutation c.869-2A>G - Family 3: heterozygous frameshift insertion c.1640dup in NEK1 together with a heterozygous missense variant in DYNC2H1

Digenic/oligogenic inheritance. A distinctive etiologic feature of SRTD6 is documented digenic diallelic inheritance: a proband can be affected by combined heterozygosity for one loss-of-function NEK1 allele and one pathogenic DYNC2H1 allele, producing "combined haploinsufficiency of cilia formation and intraflagellar transport (IFT)" (Thiel et al. 2011). This was substantiated in a larger follow-up cohort: El Hokayem et al. (J Med Genet 2012, PMID:22499340) screened 13 SRP type II (Majewski) and 7 SRP type IV (Beemer-Langer) cases, finding homozygous NEK1 mutations in 5/13 type II cases, compound heterozygous DYNC2H1 mutations in 4/12 type II cases, and one case with double heterozygosity across both genes — while both genes were excluded in all type IV (Beemer-Langer) cases, establishing that NEK1/DYNC2H1 involvement is specific to the Majewski subtype. The authors noted residual genetic heterogeneity, since neither gene explained all screened cases, implying additional unidentified causal genes remain. Mutation-negative SRP type II cases in that cohort notably presented with holoprosencephaly and polymicrogyria, absent in mutation-positive cases — suggesting phenotypic clues to underlying gene.

Risk factors: - Genetic: consanguinity substantially raises risk given the autosomal recessive, homozygous-null mechanism seen in the founding families. - Environmental: No environmental, infectious, or lifestyle risk factors are established; this is a purely monogenic/digenic ciliopathy. - Gene-environment interaction: None reported.

Protective factors: None specifically described for SRTD6. In the broader ciliopathy spectrum, allelic severity is thought to be genotype-dependent — hypomorphic (partial-function) alleles of ciliary genes generally produce milder, non-lethal SRTD phenotypes (e.g., Mainzer-Saldino, isolated Jeune-type disease) versus complete loss-of-function alleles producing lethal Majewski-type disease, though this specific genotype-severity correlation has not been formally established for NEK1 itself.

3. Phenotypes

Because SRTD6 aggregates clinical data across a small number of published families/case reports, phenotype frequencies below are qualitative characterizations from the SRTD/SRPS Majewski-type literature rather than large-cohort percentages.

Skeletal phenotype (core, congenital/prenatal onset): - Narrow, constricted thoracic cage — HP:0000774 (Narrow chest) - Short ribs — HP:0000773 (Short ribs) - Short-limbed dwarfism/micromelia — HP:0004970 (Mesomelia) / HP:0009824 (Progressive shortening of the extremities) - Disproportionately short, ovoid tibiae or tibial agenesis (the most distinctive Majewski-type finding, distinguishing it from other SRP subtypes) — HP:0005843 (Micromelia); HP:0009825 - Polydactyly (pre- and postaxial), variably present — HP:0100259 (Postaxial polydactyly) / HP:0001161 (Preaxial polydactyly) - Trident-shaped acetabular roof on radiography — HP:0003026 (Trident acetabular roof)

Craniofacial: - Dysmorphic facial features — HP:0001999 - Cleft lip/palate (part of the broader SRTD non-skeletal spectrum) — HP:0000175 (Cleft palate) / HP:0100333 (Unilateral cleft lip) - Relatively proportionate head size at birth progressing to microcephaly

Visceral/organ anomalies: - Cystic/polycystic kidney disease with dilated collecting tubules and glomeruli of variable size — HP:0000113 (Polycystic kidney dysplasia) - Intestinal malrotation — HP:0002566 - Congenital heart defects — HP:0001627 - Hepatic anomalies (periportal fibrosis, biliary dysgenesis characteristic of the broader ciliopathy spectrum) — HP:0006560 - Lingual/gingival hamartomas reported in a substantial minority of NEK1-related cases - Genital anomalies

Growth: Severe intrauterine growth restriction is characteristic of the Majewski (type II) presentation (search summary of Tonni et al. 2014, PMID:24854045).

Onset/severity/progression. Onset is prenatal/congenital in essentially all cases; the classic homozygous-null presentation is uniformly severe and lethal in the perinatal/neonatal period due to pulmonary hypoplasia secondary to the restrictive thoracic cage (respiratory insufficiency). At least one report describes "a short rib polydactyly syndrome overlapping both lethal and nonlethal types" (PMID:22876582), suggesting a phenotypic continuum exists at the milder end even within Majewski-type presentations, potentially correlating with residual NEK1/DYNC2H1 function in digenic or hypomorphic cases.

Quality of life impact. For the lethal neonatal presentation, QOL data are not applicable given perinatal mortality; for surviving/milder cases (analogous non-lethal SRTD forms), impact centers on chronic respiratory insufficiency, orthopedic disability from limb shortening, and renal/hepatic morbidity — but disease-specific QOL instruments have not been applied to this specific ultra-rare entity.

4. Genetic/Molecular Information

Causal gene: NEK1 (HGNC:7744; NCBI Gene ID 4750), OMIM *604588, chromosome 4q33.

Variant spectrum documented in the literature: | Variant | Type | Zygosity | Source | |---|---|---|---| | c.379C>T (p.Arg127X) | Nonsense | Homozygous | Thiel 2011, Family 1 | | c.869-2A>G | Splice-site (canonical acceptor) | Homozygous | Thiel 2011, Family 2 | | c.1640dup | Frameshift insertion | Heterozygous (digenic with DYNC2H1) | Thiel 2011, Family 3 | | c.2255A>G (p.Glu752Gly) | Missense | — | ClinVar RCV000625335 | | c.1020+1G>A | Splice-site | — | ClinVar RCV003106460 |

Digenic partner gene: DYNC2H1 (cytoplasmic dynein 2 heavy chain 1), OMIM 603297, encoding the retrograde IFT motor protein; biallelic DYNC2H1 mutations alone cause the allelic disorder SRTD3/short-rib polydactyly type I (Saldino-Noonan). El Hokayem et al. found compound heterozygous DYNC2H1* mutations independently causal in 4/12 SRTD6-consistent cases, and demonstrated true digenic (both-gene) inheritance in at least one further case.

Functional consequence: Loss-of-function (nonsense/frameshift/splice-disrupting) — patient fibroblasts show a severe ciliogenesis defect: only ~27% of cells possessed cilia versus 92% in controls; residual cilia averaged 1.7 ± 0.7 μm in length versus 6.2 ± 1.2 μm in controls, with a "severely reduced length, broad base, and thin apex," and electron microscopy showed ciliogenesis arrested at stage 1, preventing axoneme elongation (Thiel et al. 2011).

Allele frequency/population data: No specific gnomAD/population carrier-frequency figures for these specific pathogenic NEK1 alleles were identified in this search; NEK1 loss-of-function variants overall are not vanishingly rare in the population because they also confer risk (in monoallelic form) for a distinct, later-onset adult disease (see below), implying population-level heterozygote carriers of NEK1 LoF alleles exist at appreciable frequency, though homozygous/compound-heterozygous null combinations producing SRTD6 remain very rare.

Notable pleiotropy — NEK1 and ALS. NEK1 is independently one of the most robustly replicated ALS risk genes: heterozygous NEK1 loss-of-function variants are found in ~2–3% of both familial and sporadic amyotrophic lateral sclerosis cases (van Rheenen et al., Nat Genet 2016; Rifai et al. 2025, PMID:38986433). NEK1 is implicated in cilia formation, DNA-damage response, microtubule stability, and axonal polarity; the missense variant p.Arg261His has specifically been linked to increased ALS susceptibility, and NEK1 loss-of-function has been shown to induce DNA damage accumulation in ALS patient-derived motor neurons (Higelin et al. 2018, PMID:29929116) and to disrupt microtubule homeostasis/nuclear import (PMC10431718). This represents an important gene-dosage relationship for curation purposes: monoallelic NEK1 LoF → ALS susceptibility in adults; biallelic (or digenic NEK1+DYNC2H1) LoF → lethal perinatal skeletal ciliopathy (SRTD6).

Epigenetics/chromosomal abnormalities: No epigenetic mechanism or large chromosomal rearrangement mechanism has been described for SRTD6; it is a classical biallelic point-mutation/small-indel Mendelian disorder.

5. Environmental Information

No environmental toxins, lifestyle factors, or infectious triggers are documented as contributing to SRTD6 — it is a fully genetically determined ciliopathy with no reported gene-environment modulation.

6. Mechanism / Pathophysiology

Molecular pathway: NEK1 is a NIMA-family serine/threonine kinase that localizes to the centrosome and basal body of the primary cilium and is required for the initiation and elongation of ciliogenesis. Together with its digenic partner DYNC2H1 (the motor subunit of cytoplasmic dynein-2, which drives retrograde intraflagellar transport, IFT), NEK1 loss disrupts both the assembly and the trafficking machinery of the primary cilium.

Causal chain (upstream → downstream): 1. Molecular trigger: Biallelic loss-of-function NEK1 variants (or digenic NEK1+DYNC2H1 haploinsufficiency) abolish or truncate functional NEK1 kinase. 2. Cellular process: Ciliogenesis is arrested at an early stage (stage 1 by EM), producing severely reduced cilium number and grossly abnormal (short, broad-based, thin-apex) cilium morphology in patient fibroblasts. 3. Tissue/organ process: Impaired Hedgehog and other cilium-dependent signaling in the growth plate disrupts endochondral ossification, producing shortened long bones, short ribs, and the constricted trident-shaped thoracic skeleton; impaired ciliary signaling in the kidney nephron produces cystic dilatation of tubules/glomeruli; impaired ciliary signaling during organogenesis produces situs/laterality-adjacent defects such as intestinal malrotation and congenital heart defects. 4. Organism-level outcome: The severely restricted thoracic cage causes pulmonary hypoplasia and, in the classic lethal presentation, fatal neonatal respiratory insufficiency.

Cell types/biological processes involved: - Chondrocytes and growth-plate cells (GO:0001501 skeletal system development; GO:0060173 limb development) — CL:0000138 chondrocyte - Ciliated epithelial cells across multiple organs (GO:0060271 cilium assembly; GO:0003341 cilium movement) - Renal tubular epithelial cells (CL:1000838 kidney collecting duct principal cell / general nephron epithelium) - Centrosome/basal body machinery (GO:0005929 cilium; GO:0005813 centrosome)

Protein dysfunction: NEK1 truncating/nonsense/splice variants are predicted to produce a nonfunctional or absent kinase; DYNC2H1 missense/compound-heterozygous variants impair motor-protein function within the IFT-B/dynein-2 retrograde transport complex.

Molecular profiling / advanced omics: No transcriptomic, proteomic, single-cell, or spatial-omics dataset specific to SRTD6/NEK1 patient tissue was identified in this search; the mechanistic evidence base rests on classic cellular/EM ciliary phenotyping in patient-derived fibroblasts (Thiel et al. 2011) rather than -omics profiling.

7. Anatomical Structures Affected

Organ level: - Primary: skeletal system (rib cage, long bones, pelvis/acetabulum), lungs (secondary hypoplasia) - Secondary/associated: kidneys (cystic dysplasia), liver, intestines (malrotation), heart, oral cavity (lingual/gingival hamartomas), craniofacial structures (cleft lip/palate) - Body systems: skeletal, respiratory, renal, hepatobiliary, gastrointestinal, cardiovascular

Tissue/cell level: Cartilage and growth-plate chondrocytes (endochondral bone), renal tubular/glomerular epithelium, ciliated epithelial cell populations broadly (UBERON:0000922 embryonic structures during organogenesis are relevant given the developmental timing).

Subcellular level: Primary cilium and basal body/centrosome (GO:0005929 cilium; GO:0036064 ciliary basal body; GO:0005813 centrosome) — the direct organelle-level site of NEK1/DYNC2H1 dysfunction.

Anatomical terms (UBERON): - UBERON:0002228 rib - UBERON:0002228 thoracic cage / UBERON:0000915 thoracic segment - UBERON:0002203 pelvic girdle / acetabulum - UBERON:0002113 kidney - UBERON:0002370 thymus (not specifically implicated but general organogenesis context) - UBERON:0002049 tibia

Laterality: No consistent lateralization pattern reported; skeletal changes are typically bilateral/symmetric, consistent with a systemic skeletal dysplasia rather than a focal or asymmetric process.

8. Temporal Development

• Onset: Congenital/prenatal — detectable by second-trimester ultrasound (short-limb dwarfism, narrow thorax, polydactyly).
• Onset pattern: Present from early fetal development; not acquired or adult-onset in the classic SRTD6 presentation.
• Progression: In the lethal (classic biallelic-null) form, the disease is present at birth and rapidly fatal in the neonatal period from respiratory failure; there is no "stage" progression in a clinical-course sense — it is a fixed developmental malformation syndrome rather than a degenerative disease.
• Course pattern: Non-progressive skeletal malformation with static structural anomalies; the acute driver of mortality is respiratory insufficiency at or shortly after birth.
• Duration: For the lethal type, self-limited by neonatal death; case reports of milder "overlapping lethal/nonlethal" phenotypes suggest occasional survivors, in which case the skeletal features would presumably persist as a chronic, non-progressive dysplasia (as in analogous non-lethal SRTD entities such as Jeune syndrome, where survivors can have chronic thoracic insufficiency).
• Critical periods: Second-trimester prenatal ultrasound is the key window for detection; the perinatal period is the critical window of vulnerability for respiratory mortality.

9. Inheritance and Population

Epidemiology: No SRTD6-specific incidence figure was located; the short-rib thoracic dysplasia group as a whole (encompassing Jeune/asphyxiating thoracic dystrophy, the SRPS types, Mainzer-Saldino, and Ellis-van Creveld) is estimated at 1:100,000 to 1:130,000 live births (search summary citing SRTD group literature; consistent with Jeune-syndrome-specific figures at NORD). SRTD6/Majewski-type specifically is a small fraction of this pool — the discovery and follow-up cohorts each comprised only a handful to ~13-20 families.

Inheritance pattern: Autosomal recessive (biallelic NEK1), with documented digenic diallelic inheritance (heterozygous NEK1 + heterozygous DYNC2H1) as an alternative genetic architecture in some families — an important nuance beyond simple monogenic AR inheritance.

Penetrance/expressivity: The classic homozygous/compound-heterozygous null genotype appears fully penetrant for the lethal phenotype; variable expressivity is suggested by reports of milder/non-lethal overlap phenotypes (PMID:22876582), potentially reflecting hypomorphic alleles or digenic combinations with partial residual function.

Consanguinity: The founding genetic mapping studies used consanguineous families (homozygosity mapping design), consistent with an increased risk in consanguineous unions given the rare recessive allele frequency.

Founder effects/carrier frequency/geographic distribution: No specific founder mutation or population-enriched carrier frequency was identified for SRTD6-causing NEK1 alleles in this search.

Demographics: No sex ratio skew is reported (autosomal, not X-linked); affected individuals are, by definition, prenatal/neonatal in age given the classic lethal presentation.

10. Diagnostics

Prenatal imaging: Second- and third-trimester ultrasound is the primary diagnostic modality — short/micromelic long bones, narrow thorax, polydactyly, and (in Majewski type specifically) disproportionately short/ovoid tibiae are characteristic findings (Tonni et al. 2014, PMID:24854045; prenatal case series ScienceDirect 2012).

Postnatal/autopsy radiography: Short horizontal ribs, "trident" acetabular roof, shortened tubular bones — the classic radiographic constellation defining the SRTD/SRPS group and distinguishing Majewski (type II) from Saldino-Noonan (type I), Verma-Naumoff (type III), and Beemer-Langer (type IV) by specific limb-bone morphology (particularly tibial involvement in Majewski type).

Histopathology: Chondral growth-plate histology and renal/hepatic histopathology have been characterized in autopsy/prenatal-diagnosis case series (Tonni et al. 2014, PMC2890924).

Genetic testing: - Single-gene NEK1 sequencing or NEK1+DYNC2H1 dual testing given documented digenic inheritance - Skeletal dysplasia/ciliopathy gene panels (which would include NEK1, DYNC2H1, and other SRTD genes — the field now recognizes ~25 genes across the skeletal ciliopathy spectrum) - Exome/genome sequencing, particularly valuable given genetic heterogeneity within SRP type II (only ~9/13 cases explained by NEK1 or DYNC2H1 in the largest published cohort) and the possibility of digenic combinations that single-gene panels might miss if not designed to flag compound findings across two genes - Chromosomal microarray/karyotype are not primary diagnostic tools here (this is not a copy-number or aneuploidy disorder)

Differential diagnosis: Other SRTD/SRPS subtypes (Saldino-Noonan/type I, Verma-Naumoff/type III, Beemer-Langer/type IV), Ellis-van Creveld syndrome, Jeune syndrome (asphyxiating thoracic dystrophy), Mainzer-Saldino syndrome, and other lethal skeletal dysplasias (e.g., thanatophoric dysplasia) presenting with narrow thorax and limb shortening on prenatal ultrasound — differentiation is largely radiographic (limb-bone pattern) plus molecular confirmation (MDPI 2022 differential-diagnosis case report).

Screening: No population-based newborn or carrier screening program specific to SRTD6 exists; detection is via targeted prenatal ultrasound in at-risk (e.g., consanguineous or previously affected) families, followed by confirmatory molecular testing.

11. Outcome/Prognosis

Mortality: The classic (biallelic-null) SRTD6/Majewski-type presentation is lethal in the neonatal period, with death from respiratory insufficiency secondary to pulmonary hypoplasia driven by the severely restricted thoracic cage — consistent with SRP types 1–4 broadly being "lethal in the newborn period because of severe pulmonary hypoplasia and other associated anomalies."

Milder/overlap phenotypes: At least one report describes a short rib-polydactyly phenotype "overlapping both lethal and nonlethal types" (PMID:22876582), indicating that the digenic or hypomorphic-allele end of the spectrum may permit survival, analogous to surviving forms of the broader SRTD group (e.g., Jeune syndrome, where children can survive infancy but face chronic thoracic insufficiency and progressive renal/hepatic disease).

Prognostic factors: Genotype severity (complete null biallelic NEK1 vs. digenic/hypomorphic combinations) likely drives the lethal-vs-survivable distinction, though this has not been formally quantified in a genotype-phenotype correlation study for SRTD6 specifically.

12. Treatment

There is no disease-modifying or curative therapy for SRTD6; management is supportive and, for survivors of the perinatal period (extrapolating from the broader Jeune-syndrome/SRTD survivor literature), centers on mechanical thoracic expansion.

• Respiratory support: Mechanical ventilation for neonatal respiratory insufficiency (NCIT term: supportive care).
• Thoracic expansion surgery for thoracic insufficiency syndrome in surviving SRTD patients (established chiefly in Jeune syndrome, the closest well-studied analog):
• Vertical Expandable Prosthetic Titanium Rib (VEPTR) — FDA-approved 2004, an adjustable device that separates ribs and straightens the spine to permit lung growth; reported survival ~68% in treated Jeune-syndrome cohorts versus 70–80% mortality historically without treatment (PMID:25575358). NCIT term: NCIT:C15329 (Surgical Procedure); therapeutic modality: DEVICE.
• Lateral thoracic expansion, vertical thoracic expansion, sternal/rib elevation, and progressive internal sternal distraction techniques have all been reported, with no consensus on optimal timing/approach given disease rarity (PMC10562558).
• Renal management: Supportive care/monitoring for cystic kidney disease; dialysis/transplantation would be considered in survivors with progressive renal failure (extrapolated from the general ciliopathy-nephropathy paradigm).
• Orthopedic/rehabilitative care: For limb-shortening sequelae in survivors — NCIT:C15302 (Physical Therapy).
• Genetic counseling: NCIT:C15240 — essential given autosomal recessive/digenic inheritance and high recurrence risk (25% for simple AR; more complex for digenic combinations) in future pregnancies.
• No pharmacotherapy, gene therapy, or targeted molecular therapy has been developed or trialed specifically for NEK1-related ciliopathy; ClinicalTrials.gov searches did not surface active SRTD6-specific interventional trials in this search.

13. Prevention

• Prenatal diagnosis/reproductive options: Given the poor prognosis of the classic lethal phenotype, second-trimester ultrasound screening in at-risk families (prior affected child, known consanguinity, known carrier status) enables early prenatal diagnosis and informed reproductive decision-making.
• Carrier/genetic counseling: Recommended for families with a prior affected pregnancy or child, particularly given the digenic (NEK1+DYNC2H1) inheritance pattern, which complicates simple recurrence-risk counseling beyond standard 25% AR recurrence.
• Preimplantation genetic testing (PGT-M): A theoretically applicable option for known-carrier couples, though no SRTD6-specific PGT case series was identified.
• No primary (population-level), immunization-based, or public-health prevention strategy applies, as this is a rare monogenic/digenic disorder with no modifiable environmental component.

14. Other Species / Natural Disease

No naturally occurring SRTD6/Majewski-type ciliopathy has been reported in non-human species in this search; this appears to be a human-specific clinical entity in the veterinary/comparative literature reviewed.

15. Model Organisms

Mouse model — Nek1^kat2J^ (the "kat" mouse, for kidney, anemia, testis phenotype): - A spontaneous Nek1-null mouse mutant (kat2J allele) is the principal genetic model connecting Nek1 loss to ciliopathy phenotypes. Nek1 localizes to centrosomes and the primary cilium in this model, and kat2J homozygous mice develop polycystic kidney disease: kidney development is aberrant early, prior to gross cyst appearance — cortical zones are thin, populated by immature glomeruli, with excessive apoptosis across several cell types; cysts subsequently form postnatally in Bowman's space and multiple tubular subtypes (PMC4422189; Springer 2014). - Nek1 expression in the embryonic kidney is most prominent in cells destined to become podocytes and proximal tubules. - This model is explicitly framed in the primary literature as modeling "the ciliopathy polycystic kidney disease caused by abnormal ciliary structure or signaling" and directly links Nek1 mutation to a human ciliopathy (short-rib polydactyly syndrome type Majewski). - Limitation: The kat2J mouse model's published phenotyping emphasizes the renal cystic phenotype rather than the full skeletal (short-rib/short-limb/polydactyly) phenotype defining human SRTD6 — i.e., it recapitulates the ciliopathy/renal-cystic component with apparent fidelity but the mouse literature reviewed here does not establish whether it reproduces the diagnostic skeletal dysplasia, representing an open human-model-fidelity question for the skeletal component specifically. No dedicated skeletal-phenotyping publication for kat2J mice was surfaced in this search. - Cellular models: Patient-derived dermal fibroblasts are the key human cellular model used to establish the ciliogenesis defect (severely reduced cilium number/length, arrested ciliogenesis at stage 1) — this is IN_VITRO evidence directly from affected individuals, distinct from the mouse model (Thiel et al. 2011). - No zebrafish, Drosophila, C. elegans, iPSC-derived, or organoid model specific to NEK1-related SRTD6 was identified in this search (note: zebrafish morpholino/CRISPR knockdown of nek1 has been used in some ciliopathy contexts more broadly, but a dedicated citation was not surfaced here and should be verified against primary literature before curation).

Suggested Cell Ontology/model terms: CL:0000057 (fibroblast, for the patient-fibroblast ciliogenesis assay); NCBITaxon:10090 (Mus musculus, for the kat2J model); NCBITaxon:9606 (Homo sapiens, for fibroblast studies).

Summary of Key Ontology Term Suggestions for Curation

Sources

• Entry #263520 — SHORT-RIB THORACIC DYSPLASIA 6 WITH OR WITHOUT POLYDACTYLY; SRTD6 - OMIM
• NEK1 mutations cause short-rib polydactyly syndrome type Majewski — PubMed (PMID:21211617) / PMC3014367
• NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases — PubMed (PMID:22499340)
• Short rib-polydactyly syndrome type II (Majewski): Prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene — ScienceDirect
• Majewski syndrome (short-rib polydactyly syndrome type II): Prenatal diagnosis and histological features — PubMed (PMID:24854045)
• A short rib polydactyly syndrome overlapping both lethal and nonlethal types — PubMed (PMID:22876582)
• short-rib thoracic dysplasia 6 with or without polydactyly — Disease Ontology Browser, DOID:0110092 (JAX/MGI)
• Short-rib thoracic dysplasia 6 with or without polydactyly — NIH Genetic Testing Registry (GTR), C0024507
• NM_001199397.3(NEK1):c.2255A>G (p.Glu752Gly) — ClinVar RCV000625335
• NM_001199397.3(NEK1):c.1020+1G>A — ClinVar RCV003106460
• Expression of Nek1 during kidney development and cyst formation in the Nek1-deficient kat2J mouse model of PKD — PMC4422189 / Journal of Biomedical Science
• NEK1 variants confer susceptibility to amyotrophic lateral sclerosis — Nature Genetics
• Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis — PMC11669413 / PubMed (PMID:38986433)
• NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons — PubMed (PMID:29929116)
• Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import — PMC10431718
• Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius VEPTR — PubMed (PMID:25575358)
• A simple and reliable approach for progressive internal distraction of the sternum for Jeune syndrome — PMC10562558
• Asphyxiating Thoracic Dystrophy — NORD
• Short-Rib Thoracic Dysplasia (SRTD) — Springer Nature reference work
• Prenatal Diagnosis of Jeune Syndrome — differential diagnosis of lethal skeletal dysplasias — MDPI Genes 2022
• MONDO term lookup via OLS4 API (EBI): MONDO:0009894

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Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

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• PMID:21211617 (abstract only): "combined haploinsufficiency of cilia formation and intraflagellar transport (IFT)"
• closest text in source: "We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo"
• PMID:22876582 (abstract only): "overlapping both lethal and nonlethal types"
• closest text in source: "SRPSs are a continuous spectrum of both lethal and nonlethal forms"