McKusick-Kaufman syndrome

Mendelian MONDO:0009367 Pathograph 10 Ciliopathy

McKusick-Kaufman syndrome (MKKS) is an autosomal recessive multiple congenital anomaly syndrome classically comprising the triad of hydrometrocolpos, postaxial polydactyly, and congenital heart disease. It is caused by biallelic variants in the MKKS gene, which is the same chaperonin-like BBSome assembly gene known as BBS6. McKusick-Kaufman syndrome is therefore allelic to Bardet-Biedl syndrome 6 and is a "BBSome-opathy": on the shared BBSome trafficking pathway it represents the limb (Hedgehog) and genitourinary developmental branches, classically without the retinal dystrophy and obesity that define Bardet-Biedl syndrome. Because the two conditions overlap, an early McKusick-Kaufman diagnosis can be reclassified as Bardet-Biedl syndrome once retinopathy or obesity emerge on follow-up.

Ask OpenScientist

Ask a research question about McKusick-Kaufman syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Mappings
1
Inheritance
6
Pathophys.
7
Phenotypes
2
Gaps
10
Pathograph
1
Genes
3
Medical Actions
1
Differentials
5
References
🏷

Classifications

Harrison's Chapter
GENETICS_ENVIRONMENT_DISEASE
Mechanistic Nosology
ciliopathy
🔗

Mappings

MONDO
MONDO:0009367 McKusick-Kaufman syndrome
skos:exactMatch MONDO
Primary MONDO disease identifier for McKusick-Kaufman syndrome.
MONDO:1040050 MKKS-related ciliopathy Not Yet Curated
skos:relatedMatch MONDO
Per-locus MONDO node spanning the MKKS allelic series (McKusick-Kaufman syndrome and Bardet-Biedl syndrome 6); the join between this entry and BBS at the MKKS locus.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
McKusick-Kaufman syndrome is inherited in an autosomal recessive pattern, most frequently in the Old Order Amish founder population, with reduced penetrance and variable expressivity.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:15266619 SUPPORT Human Clinical
"a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern"
States the autosomal recessive inheritance of the McKusick-Kaufman triad.
PMID:9467007 SUPPORT Human Clinical
"This syndrome is diagnosed most frequently in the Old Order Amish population and is inherited in an autosomal recessive pattern with reduced penetrance and variable expressivity."
Documents autosomal recessive inheritance, the Old Order Amish founder population, and reduced penetrance / variable expressivity.
?

Discussions and Knowledge Gaps

2
Can MKKS/BBS6 genotype predict whether a patient will manifest the McKusick-Kaufman-restricted phenotype (limb + genitourinary) versus full Bardet-Biedl syndrome, and can the two be distinguished in the neonatal period?
KNOWLEDGE GAP OPEN gap_mkks_genotype_phenotype_mks_vs_bbs
Attached to
pathophysiology#MKKS chaperonin assembly defect pathophysiology#BBSome-dependent ciliary cargo trafficking failure
The Mkks-null mouse supports a mechanistic model in which complete loss of function produces Bardet-Biedl syndrome while specific (hypomorphic) missense alleles produce the McKusick-Kaufman-restricted phenotype. At the human clinical level, however, no reliable genotype-phenotype correlation has been established and the McKusick-Kaufman triad cannot be reliably differentiated from neonatal Bardet-Biedl syndrome, so an early McKusick-Kaufman diagnosis may be reclassified as Bardet-Biedl syndrome on follow-up. Whether allele type, modifiers, or oligogenic load resolve this is unresolved.
Show evidence (3 references)
PMID:15772095 SUPPORT Model Organism
"These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations."
Provides the model-organism basis for the null-vs-missense allelic hypothesis while leaving the human genotype-phenotype prediction open.
PMID:22090721 SUPPORT Human Clinical
"HMC, CHD, and PAP defects can also occur in BBS-6, and there is a significant clinical overlap between MKS and BBS-6 in childhood."
Documents the significant childhood clinical overlap that prevents reliable early differentiation of McKusick-Kaufman from Bardet-Biedl.
PMID:26900326 SUPPORT Human Clinical
"Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings."
An MKKS/BBS6 allele producing only RP and polydactyly demonstrates that the MKKS allelic series is a continuum without a clean genotype-phenotype boundary between McKusick-Kaufman and Bardet-Biedl.
Does the non-ciliary BBS6 nuclear-cytoplasmic transport / SMARCC1 chromatin-remodeling defect actually drive congenital heart disease in human McKusick-Kaufman syndrome patients, as it does in the zebrafish and cell models?
HUMAN MODEL MISMATCH OPEN mismatch_mkks_noncilliary_chd_human_fidelity
Attached to
pathophysiology#Non-ciliary BBS6 nuclear-cytoplasmic transport defect phenotype#Congenital heart disease
The nuclear-cytoplasmic transport / SMARCC1 mechanism for MKS congenital heart disease is demonstrated in zebrafish and in cell-based assays of the MKS-associated BBS6 H84Y;A242S allele, but its fidelity to human cardiac morphogenesis is not yet established. This is a HUMAN_MODEL_MISMATCH rather than a generic knowledge gap: a specific non-ciliary mechanism exists in model systems, and the open question is its translational validity to the human heart defect.
Proposed experiments
Test the BBS6 nuclear-transport/SMARCC1 axis in human cardiac models
exp_mkks_chd_human_cardiac_tissue
Use patient-derived or genome-edited human iPSC-cardiomyocytes / cardiac organoids carrying the MKS BBS6 H84Y;A242S allele to test whether BBS6 nuclear-cytoplasmic transport and SMARCC1-dependent chromatin remodeling are perturbed and whether cardiac differentiation/morphogenesis is affected, establishing or refuting human relevance of the model-system mechanism.
Show evidence (1 reference)
PMID:28753627 SUPPORT Model Organism
"Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients"
Provides the model-system mechanism whose human cardiac fidelity is the open question.
⚙

Pathophysiology

6
MKKS chaperonin assembly defect
Biallelic MKKS/BBS6 variants impair the chaperonin-like BBS assembly complex required to build the BBSome. MKKS/BBS6 is a divergent Group II chaperonin-like protein derived from the eukaryotic chaperonin CCT/TRiC that resides largely in the pericentriolar material around the centrioles; disease-causing mutants adopt an abnormal conformation, fail to localize to the centrosome, and are degraded by CHIP-mediated ubiquitination. The same protein additionally has a distinct non-ciliary nuclear-cytoplasmic transport function (see downstream).
MKKS hgnc:7108
pericentriolar material GO:0000242
Downstream
Defective BBSome assembly Loss of the chaperonin complex prevents BBSome assembly.
Non-ciliary BBS6 nuclear-cytoplasmic transport defect Beyond its chaperonin/basal-body role, the same MKKS/BBS6 protein has a distinct non-ciliary nuclear-cytoplasmic shuttling function whose disruption by the MKS allele underlies the congenital heart disease.
Show evidence (3 references)
PMID:22500027 SUPPORT In Vitro
"Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a complex termed the BBS-chaperonin complex. This complex is required for BBSome assembly."
Establishes MKKS/BBS6 as part of the chaperonin complex required for BBSome assembly, the proximal lesion shared with Bardet-Biedl syndrome.
PMID:15731008 SUPPORT In Vitro
"the majority of BBS6 resides within the pericentriolar material (PCM)"
Localizes the MKKS/BBS6 chaperonin to the pericentriolar material around the centrioles, the basal-body-associated site of its ciliary function.
PMID:18094050 SUPPORT In Vitro
"These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of MKKS/BBS diseases"
Identifies misfolding and CHIP-mediated degradation of disease-causing MKKS mutants as the cellular lesion underlying loss of BBS6 function.
Defective BBSome assembly
Without the chaperonin complex the obligate BBSome cannot be assembled.
BBSome GO:0034464
Downstream
BBSome-dependent ciliary cargo trafficking failure An unassembled BBSome cannot traffic ciliary cargo.
Show evidence (1 reference)
PMID:31303482 SUPPORT In Vitro
"We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex."
The obligate, interconnected BBSome cannot form when assembly is impaired.
BBSome-dependent ciliary cargo trafficking failure
Loss of BBSome-dependent ciliary trafficking disrupts cilium-dependent developmental signaling; in McKusick-Kaufman syndrome the consequences are expressed mainly in the limb and genitourinary developmental fields.
protein localization to cilium GO:0061512 ⚠ ABNORMAL
primary cilium GO:0005929
Downstream
Altered Sonic hedgehog-dependent limb patterning Cilium-dependent Hedgehog signaling failure perturbs limb-bud patterning.
Genitourinary developmental defect Cilium-dependent developmental signaling failure perturbs Mullerian/genitourinary development.
Show evidence (1 reference)
PMID:36699005 SUPPORT Model Organism
"GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet-Biedl syndrome, with GPCRs failing to localize to cilia, indicating the Bardet-Biedl syndrome proteins are required for trafficking of G protein-coupled receptors into neuronal cilia."
Demonstrates the conserved BBSome-dependent ciliary trafficking failure shared across the BBSome-opathies.
Altered Sonic hedgehog-dependent limb patterning
Loss of cilium-dependent Sonic hedgehog signaling during limb-bud development predisposes to postaxial digit duplication.
smoothened signaling pathway GO:0007224
limb bud UBERON:0004347
Downstream
Postaxial polydactyly Disrupted limb-bud patterning manifests as postaxial extra digits.
Show evidence (1 reference)
PMID:18381349 SUPPORT Model Organism
"We evaluated zebrafish fin bud patterning and observed altered Sonic hedgehog (shh) expression and subsequent changes to fin skeletal elements."
Supports altered hedgehog-dependent limb patterning as the mechanistic basis for the postaxial polydactyly shared by BBS and McKusick-Kaufman.
Genitourinary developmental defect
Cilium-dependent developmental signaling failure produces the Mullerian/genitourinary anomalies of McKusick-Kaufman syndrome, classically hydrometrocolpos in females.
female reproductive system UBERON:0000474
Downstream
Hydrometrocolpos The genitourinary developmental defect manifests as hydrometrocolpos.
Show evidence (1 reference)
PMID:15266619 SUPPORT Human Clinical
"a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern"
Documents hydrometrocolpos as a defining genitourinary feature of the McKusick-Kaufman triad.
Non-ciliary BBS6 nuclear-cytoplasmic transport defect
The congenital heart disease of McKusick-Kaufman syndrome appears to arise from a non-ciliary function of BBS6, distinct from its BBSome/ciliary role: BBS6 is actively shuttled between cytoplasm and nucleus, where it interacts with the SWI/SNF chromatin-remodeling protein SMARCC1, and the MKS-associated allele is defective in this transport while preserving cilia function. Perturbation of this nuclear-cytoplasmic / chromatin-remodeling axis is proposed to underlie the congenital heart defects that distinguish MKS from the largely cilia-driven Bardet-Biedl syndrome. NOTE: this mechanism is established in zebrafish and cell models; its fidelity to human cardiac morphogenesis remains to be confirmed (see the HUMAN_MODEL_MISMATCH discussion).
cardiomyocyte CL:0000746
nucleocytoplasmic transport GO:0006913 ⚠ ABNORMAL chromatin remodeling GO:0006338 ⚠ ABNORMAL heart development GO:0007507 ⚠ ABNORMAL
nucleus GO:0005634
Downstream
Congenital heart disease Disrupted BBS6 nuclear transport and chromatin remodeling perturbs cardiac morphogenesis.
Show evidence (3 references)
PMID:28753627 SUPPORT Model Organism
"Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects"
Establishes that the MKS allele of BBS6 produces a distinct, CHD-predominant phenotype separate from the cilia-driven BBS phenotype.
PMID:28753627 SUPPORT In Vitro
"We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport"
Shows the MKS-associated allele is specifically defective in BBS6 nuclear-cytoplasmic transport.
PMID:28753627 SUPPORT Model Organism
"Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients"
Links the BBS6 nuclear-cytoplasmic transport defect to the congenital heart disease mechanism in MKS.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for McKusick-Kaufman 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.
●

Phenotypes

7
Cardiovascular 1
Congenital heart disease Abnormal heart morphology HP:0001627
Show evidence (2 references)
PMID:12107442 SUPPORT Human Clinical
"McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome"
Lists congenital heart defects as a defining component of the McKusick-Kaufman triad.
PMID:20301675 SUPPORT Human Clinical
"A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation"
GeneReviews enumerates the spectrum of congenital heart defects in MKS.
Genitourinary 2
Hypospadias Hypospadias HP:0000047
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee)"
Hypospadias is one of the characteristic male genital malformations of MKS.
Cryptorchidism Cryptorchidism HP:0000028
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee)"
Cryptorchidism is one of the characteristic male genital malformations of MKS.
Limbs 1
Postaxial polydactyly Postaxial polydactyly HP:0100259
Show evidence (1 reference)
PMID:12107442 SUPPORT Human Clinical
"McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome"
Lists polydactyly as a defining component of the McKusick-Kaufman triad.
Other 3
Hydrometrocolpos Hydrometrocolpos HP:0030010
Show evidence (1 reference)
PMID:12107442 SUPPORT Human Clinical
"McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome"
Lists hydrometrocolpos as a defining component of the McKusick-Kaufman triad.
Atrioventricular canal defect Atrioventricular canal defect HP:0006695
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation"
Atrioventricular canal defect is specifically enumerated among MKS congenital heart defects.
Chordee Chordee HP:0000041
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee)"
Chordee is one of the characteristic male genital malformations of MKS.
🧬

Genetic Associations

1
MKKS (Pathogenic biallelic variants)
Gene: MKKS hgnc:7108
Show evidence (5 references)
PMID:12107442 SUPPORT Human Clinical
"both syndromes are caused by mutations in the MKKS gene"
Directly states that McKusick-Kaufman syndrome and Bardet-Biedl syndrome are both caused by MKKS mutations, establishing allelism.
PMID:10802661 SUPPORT Human Clinical
"The MKKS predicted protein shows amino acid similarity to the chaperonin family of proteins, suggesting a role for protein processing in limb, cardiac and reproductive system development."
The gene-identification study shows MKKS is a chaperonin-like protein and links its function to limb, cardiac, and reproductive development - the three branches of the McKusick-Kaufman triad.
PMID:15772095 SUPPORT Model Organism
"These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations."
The Mkks-null mouse supports the allelic model that complete loss of function yields Bardet-Biedl syndrome whereas specific missense mutations yield the McKusick-Kaufman-restricted phenotype.
+ 2 more references
💊

Medical Actions

3
Surgical correction of hydrometrocolpos and malformations
Action: surgical procedure MAXO:0000004
Management is directed at the structural anomalies: surgical repair of the obstruction causing hydrometrocolpos with drainage of accumulated fluid, and standard treatment of polydactyly and congenital heart defects. Care is needed with anesthesia in the neonatal period because severe hydrometrocolpos can cause diaphragmatic compression.
Show evidence (2 references)
PMID:20301675 SUPPORT Human Clinical
"Surgical repair of the obstruction causing HMC and drainage of the accumulated fluid"
Defines the standard surgical management of hydrometrocolpos in MKS.
PMID:20301675 SUPPORT Human Clinical
"Care with anesthesia in the neonatal period as severe HMC can cause diaphragmatic compression"
GeneReviews agents/circumstances-to-avoid caution: neonatal anesthesia risk from hydrometrocolpos-related diaphragmatic compression.
Supportive and multidisciplinary care
Action: supportive care MAXO:0000950
Care is supportive and multidisciplinary, with surveillance for later complications of hydrometrocolpos surgery and ongoing monitoring for emerging Bardet-Biedl syndrome features (vision, growth, renal, and developmental assessments).
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"ongoing surveillance for manifestations of BBS including growth and developmental assessments, ophthalmologic examination, and electroretinogram"
Supports surveillance for emerging Bardet-Biedl syndrome features in individuals diagnosed with McKusick-Kaufman syndrome.
Genetic counseling
Action: genetic counseling MAXO:0000079
Autosomal recessive inheritance entails a 25% recurrence risk for siblings; once biallelic MKKS variants are identified, carrier, prenatal, and preimplantation genetic testing become available. Counseling should note that an apparent McKusick-Kaufman diagnosis may later prove to be Bardet-Biedl syndrome.
Show evidence (1 reference)
PMID:20301675 SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected"
States the 25% sibling recurrence risk underpinning genetic counseling.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from McKusick-Kaufman syndrome:

Bardet-Biedl syndrome
Overlapping Features Bardet-Biedl syndrome is the allelic (MKKS/BBS6) condition with the greatest overlap: it shares hydrometrocolpos and polydactyly but is distinguished by age-dependent retinal dystrophy, obesity, and intellectual disability, which may be absent in infancy - so the two can be clinically indistinguishable in the neonatal period.
Show evidence (2 references)
PMID:20301675 SUPPORT Human Clinical
"an allelic condition with considerable clinical overlap and age-dependent features including retinal dystrophy, obesity, and intellectual disability"
Establishes Bardet-Biedl syndrome as the principal allelic differential, distinguished by age-dependent retinal/metabolic features.
PMID:35860126 SUPPORT Human Clinical
"retinal manifestations are a differentiating feature from MKS"
Confirms retinal involvement as the key feature distinguishing Bardet-Biedl syndrome from McKusick-Kaufman syndrome.
{ }

Source YAML

click to show 
name: McKusick-Kaufman syndrome
creation_date: "2026-06-14T00:00:00Z"
category: Mendelian
description: >-
  McKusick-Kaufman syndrome (MKKS) is an autosomal recessive multiple congenital
  anomaly syndrome classically comprising the triad of hydrometrocolpos,
  postaxial polydactyly, and congenital heart disease. It is caused by biallelic
  variants in the MKKS gene, which is the same chaperonin-like BBSome assembly
  gene known as BBS6. McKusick-Kaufman syndrome is therefore allelic to
  Bardet-Biedl syndrome 6 and is a "BBSome-opathy": on the shared BBSome
  trafficking pathway it represents the limb (Hedgehog) and genitourinary
  developmental branches, classically without the retinal dystrophy and obesity
  that define Bardet-Biedl syndrome. Because the two conditions overlap, an
  early McKusick-Kaufman diagnosis can be reclassified as Bardet-Biedl syndrome
  once retinopathy or obesity emerge on follow-up.
disease_term:
  preferred_term: McKusick-Kaufman syndrome
  term:
    id: MONDO:0009367
    label: McKusick-Kaufman syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009367
      label: McKusick-Kaufman syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for McKusick-Kaufman syndrome.
  - term:
      id: MONDO:1040050
      label: MKKS-related ciliopathy
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Per-locus MONDO node spanning the MKKS allelic series (McKusick-Kaufman
      syndrome and Bardet-Biedl syndrome 6); the join between this entry and BBS
      at the MKKS locus.
parents:
- Ciliopathy
synonyms:
- MKKS
- MKS
notes: >-
  Framed as a distinct clinical and MONDO entity that is allelic to Bardet-Biedl
  syndrome 6 (both caused by MKKS/BBS6). The MKKS↔BBS6 relationship is the
  vertical (per-locus) axis already curated by MONDO as "MKKS-related
  ciliopathy"; this entry captures the McKusick-Kaufman-specific branch subset
  (limb + genitourinary) of the shared BBSome trafficking mechanism.
  Genotype-phenotype: no reliable clinical correlation has been established and
  the McKusick-Kaufman triad cannot be reliably differentiated from neonatal
  Bardet-Biedl syndrome on clinical grounds; the leading mechanistic hypothesis
  (from the Mkks-null mouse) is that complete loss of function biases toward
  Bardet-Biedl syndrome while specific (hypomorphic) missense alleles produce the
  McKusick-Kaufman-restricted phenotype. Consequently, some patients diagnosed
  with McKusick-Kaufman syndrome in infancy are later reclassified as
  Bardet-Biedl syndrome once retinopathy or obesity emerge. McKusick-Kaufman
  syndrome is diagnosed most frequently in the Old Order Amish founder
  population, with reduced penetrance and variable expressivity.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    McKusick-Kaufman syndrome is inherited in an autosomal recessive pattern,
    most frequently in the Old Order Amish founder population, with reduced
    penetrance and variable expressivity.
  evidence:
  - reference: PMID:15266619
    reference_title: "A female with complete lack of Mullerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos
      (HMC), PAP, and congenital heart malformation that is inherited in an
      autosomal recessive pattern
    explanation: >-
      States the autosomal recessive inheritance of the McKusick-Kaufman triad.
  - reference: PMID:9467007
    reference_title: "Genetic and physical mapping of the McKusick-Kaufman syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is diagnosed most frequently in the Old Order Amish
      population and is inherited in an autosomal recessive pattern with reduced
      penetrance and variable expressivity.
    explanation: >-
      Documents autosomal recessive inheritance, the Old Order Amish founder
      population, and reduced penetrance / variable expressivity.
genetic:
- name: MKKS
  association: Pathogenic biallelic variants
  gene_term:
    preferred_term: MKKS
    term:
      id: hgnc:7108
      label: MKKS
  notes: >-
    MKKS (also known as BBS6) encodes a chaperonin-like protein required for
    BBSome assembly. The same gene causes both McKusick-Kaufman syndrome and
    Bardet-Biedl syndrome 6, making the two conditions allelic. The leading
    allelic model is that complete loss of function biases toward Bardet-Biedl
    syndrome whereas specific (hypomorphic) missense alleles produce the
    McKusick-Kaufman-restricted phenotype.
  evidence:
  - reference: PMID:12107442
    reference_title: "Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both syndromes are caused by mutations in the MKKS gene
    explanation: >-
      Directly states that McKusick-Kaufman syndrome and Bardet-Biedl syndrome
      are both caused by MKKS mutations, establishing allelism.
  - reference: PMID:10802661
    reference_title: "Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MKKS predicted protein shows amino acid similarity to the chaperonin
      family of proteins, suggesting a role for protein processing in limb,
      cardiac and reproductive system development.
    explanation: >-
      The gene-identification study shows MKKS is a chaperonin-like protein and
      links its function to limb, cardiac, and reproductive development - the
      three branches of the McKusick-Kaufman triad.
  - reference: PMID:15772095
    reference_title: "Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These observations suggest that the complete absence of MKKS leads to BBS
      while the MKS phenotype is likely to be due to specific mutations.
    explanation: >-
      The Mkks-null mouse supports the allelic model that complete loss of
      function yields Bardet-Biedl syndrome whereas specific missense mutations
      yield the McKusick-Kaufman-restricted phenotype.
  - reference: PMID:15266619
    reference_title: "A female with complete lack of Mullerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both MKS and BBS can be caused by mutations in the MKKS or BBS6 gene on
      chromosome 20p12
    explanation: >-
      Independently confirms the MKKS/BBS6 gene as the shared cause of
      McKusick-Kaufman and Bardet-Biedl syndromes.
  - reference: PMID:10973238
    reference_title: "Mutations in MKKS cause Bardet-Biedl syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found MKKS mutations in four typical BBS probands
    explanation: >-
      Establishes that MKKS mutations also cause Bardet-Biedl syndrome,
      underpinning the allelic relationship between the two disorders.
pathophysiology:
- name: MKKS chaperonin assembly defect
  conforms_to: "bbsome_trafficking#BBS Chaperonin Assembly Defect"
  description: >-
    Biallelic MKKS/BBS6 variants impair the chaperonin-like BBS assembly complex
    required to build the BBSome. MKKS/BBS6 is a divergent Group II
    chaperonin-like protein derived from the eukaryotic chaperonin CCT/TRiC that
    resides largely in the pericentriolar material around the centrioles;
    disease-causing mutants adopt an abnormal conformation, fail to localize to
    the centrosome, and are degraded by CHIP-mediated ubiquitination. The same
    protein additionally has a distinct non-ciliary nuclear-cytoplasmic transport
    function (see downstream).
  genes:
  - preferred_term: MKKS
    term:
      id: hgnc:7108
      label: MKKS
  cellular_components:
  - preferred_term: pericentriolar material
    term:
      id: GO:0000242
      label: pericentriolar material
  evidence:
  - reference: PMID:22500027
    reference_title: "Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type
      II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a
      complex termed the BBS-chaperonin complex. This complex is required for
      BBSome assembly.
    explanation: >-
      Establishes MKKS/BBS6 as part of the chaperonin complex required for
      BBSome assembly, the proximal lesion shared with Bardet-Biedl syndrome.
  - reference: PMID:15731008
    reference_title: "MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the majority of BBS6 resides within the pericentriolar material (PCM)
    explanation: >-
      Localizes the MKKS/BBS6 chaperonin to the pericentriolar material around
      the centrioles, the basal-body-associated site of its ciliary function.
  - reference: PMID:18094050
    reference_title: "MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results indicate that the MKKS mutants have an abnormal conformation
      and that chaperone-dependent degradation mediated by CHIP is a key feature
      of MKKS/BBS diseases
    explanation: >-
      Identifies misfolding and CHIP-mediated degradation of disease-causing
      MKKS mutants as the cellular lesion underlying loss of BBS6 function.
  downstream:
  - target: Defective BBSome assembly
    description: Loss of the chaperonin complex prevents BBSome assembly.
  - target: Non-ciliary BBS6 nuclear-cytoplasmic transport defect
    description: >-
      Beyond its chaperonin/basal-body role, the same MKKS/BBS6 protein has a
      distinct non-ciliary nuclear-cytoplasmic shuttling function whose
      disruption by the MKS allele underlies the congenital heart disease.
- name: Defective BBSome assembly
  conforms_to: "bbsome_trafficking#Defective BBSome Assembly"
  description: >-
    Without the chaperonin complex the obligate BBSome cannot be assembled.
  cellular_components:
  - preferred_term: BBSome
    term:
      id: GO:0034464
      label: BBSome
  evidence:
  - reference: PMID:31303482
    reference_title: "The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We find that BBSome subunits have a very high degree of interconnectivity,
      explaining the obligate nature of the complex.
    explanation: >-
      The obligate, interconnected BBSome cannot form when assembly is impaired.
  downstream:
  - target: BBSome-dependent ciliary cargo trafficking failure
    description: An unassembled BBSome cannot traffic ciliary cargo.
- name: BBSome-dependent ciliary cargo trafficking failure
  conforms_to: "bbsome_trafficking#BBSome-Dependent Ciliary Cargo Trafficking Failure"
  description: >-
    Loss of BBSome-dependent ciliary trafficking disrupts cilium-dependent
    developmental signaling; in McKusick-Kaufman syndrome the consequences are
    expressed mainly in the limb and genitourinary developmental fields.
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  biological_processes:
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36699005
    reference_title: "Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      GPCR ciliary localization is disrupted in neurons from mouse models of the
      ciliopathy Bardet-Biedl syndrome, with GPCRs failing to localize to cilia,
      indicating the Bardet-Biedl syndrome proteins are required for trafficking
      of G protein-coupled receptors into neuronal cilia.
    explanation: >-
      Demonstrates the conserved BBSome-dependent ciliary trafficking failure
      shared across the BBSome-opathies.
  downstream:
  - target: Altered Sonic hedgehog-dependent limb patterning
    description: Cilium-dependent Hedgehog signaling failure perturbs limb-bud patterning.
  - target: Genitourinary developmental defect
    description: Cilium-dependent developmental signaling failure perturbs Mullerian/genitourinary development.
- name: Altered Sonic hedgehog-dependent limb patterning
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >-
    Loss of cilium-dependent Sonic hedgehog signaling during limb-bud
    development predisposes to postaxial digit duplication.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  locations:
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  evidence:
  - reference: PMID:18381349
    reference_title: "Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We evaluated zebrafish fin bud patterning and observed altered Sonic
      hedgehog (shh) expression and subsequent changes to fin skeletal elements.
    explanation: >-
      Supports altered hedgehog-dependent limb patterning as the mechanistic
      basis for the postaxial polydactyly shared by BBS and McKusick-Kaufman.
  downstream:
  - target: Postaxial polydactyly
    description: Disrupted limb-bud patterning manifests as postaxial extra digits.
- name: Genitourinary developmental defect
  description: >-
    Cilium-dependent developmental signaling failure produces the
    Mullerian/genitourinary anomalies of McKusick-Kaufman syndrome, classically
    hydrometrocolpos in females.
  locations:
  - preferred_term: female reproductive system
    term:
      id: UBERON:0000474
      label: female reproductive system
  evidence:
  - reference: PMID:15266619
    reference_title: "A female with complete lack of Mullerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos
      (HMC), PAP, and congenital heart malformation that is inherited in an
      autosomal recessive pattern
    explanation: >-
      Documents hydrometrocolpos as a defining genitourinary feature of the
      McKusick-Kaufman triad.
  downstream:
  - target: Hydrometrocolpos
    description: The genitourinary developmental defect manifests as hydrometrocolpos.
- name: Non-ciliary BBS6 nuclear-cytoplasmic transport defect
  description: >-
    The congenital heart disease of McKusick-Kaufman syndrome appears to arise
    from a non-ciliary function of BBS6, distinct from its BBSome/ciliary role:
    BBS6 is actively shuttled between cytoplasm and nucleus, where it interacts
    with the SWI/SNF chromatin-remodeling protein SMARCC1, and the MKS-associated
    allele is defective in this transport while preserving cilia function.
    Perturbation of this nuclear-cytoplasmic / chromatin-remodeling axis is
    proposed to underlie the congenital heart defects that distinguish MKS from
    the largely cilia-driven Bardet-Biedl syndrome. NOTE: this mechanism is
    established in zebrafish and cell models; its fidelity to human cardiac
    morphogenesis remains to be confirmed (see the HUMAN_MODEL_MISMATCH
    discussion).
  biological_processes:
  - preferred_term: nucleocytoplasmic transport
    term:
      id: GO:0006913
      label: nucleocytoplasmic transport
    modifier: ABNORMAL
  - preferred_term: chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: ABNORMAL
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:28753627
    reference_title: "Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl
      syndrome (BBS), a syndrome caused by defects in cilia transport and
      function, as well as McKusick-Kaufman syndrome, a genetic disorder
      characterized by congenital heart defects
    explanation: >-
      Establishes that the MKS allele of BBS6 produces a distinct,
      CHD-predominant phenotype separate from the cilia-driven BBS phenotype.
  - reference: PMID:28753627
    reference_title: "Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that BBS6 is actively transported between the cytoplasm and
      nucleus, and that BBS6H84Y; A242S, is defective in this transport
    explanation: >-
      Shows the MKS-associated allele is specifically defective in BBS6
      nuclear-cytoplasmic transport.
  - reference: PMID:28753627
    reference_title: "Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our work identifies a new function for BBS6 in nuclear-cytoplasmic
      transport, and provides insight into the disease mechanism underlying the
      congenital heart defects in McKusick-Kaufman syndrome patients
    explanation: >-
      Links the BBS6 nuclear-cytoplasmic transport defect to the congenital
      heart disease mechanism in MKS.
  downstream:
  - target: Congenital heart disease
    description: Disrupted BBS6 nuclear transport and chromatin remodeling perturbs cardiac morphogenesis.
phenotypes:
- name: Postaxial polydactyly
  category: Skeletal
  diagnostic: true
  description: >-
    Postaxial extra digits are a cardinal feature of the McKusick-Kaufman triad.
  phenotype_term:
    preferred_term: postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:12107442
    reference_title: "Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and
      congenital heart defects and overlaps with Bardet-Biedl syndrome
    explanation: >-
      Lists polydactyly as a defining component of the McKusick-Kaufman triad.
- name: Hydrometrocolpos
  category: Genitourinary
  diagnostic: true
  description: >-
    Hydrometrocolpos (accumulation of fluid in the vagina and uterus) is the
    defining genitourinary feature in affected females.
  phenotype_term:
    preferred_term: hydrometrocolpos
    term:
      id: HP:0030010
      label: Hydrometrocolpos
  evidence:
  - reference: PMID:12107442
    reference_title: "Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and
      congenital heart defects and overlaps with Bardet-Biedl syndrome
    explanation: >-
      Lists hydrometrocolpos as a defining component of the McKusick-Kaufman
      triad.
- name: Congenital heart disease
  category: Cardiovascular
  description: >-
    Congenital heart malformation completes the classic McKusick-Kaufman triad.
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:12107442
    reference_title: "Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and
      congenital heart defects and overlaps with Bardet-Biedl syndrome
    explanation: >-
      Lists congenital heart defects as a defining component of the
      McKusick-Kaufman triad.
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variety of congenital heart defects have been reported including
      atrioventricular canal, atrial septal defect, ventricular septal defect,
      or a complex congenital heart malformation
    explanation: >-
      GeneReviews enumerates the spectrum of congenital heart defects in MKS.
- name: Atrioventricular canal defect
  category: Cardiovascular
  description: >-
    Atrioventricular canal (endocardial cushion) defect is among the reported
    congenital heart malformations in McKusick-Kaufman syndrome.
  phenotype_term:
    preferred_term: Atrioventricular canal defect
    term:
      id: HP:0006695
      label: Atrioventricular canal defect
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variety of congenital heart defects have been reported including
      atrioventricular canal, atrial septal defect, ventricular septal defect,
      or a complex congenital heart malformation
    explanation: >-
      Atrioventricular canal defect is specifically enumerated among MKS
      congenital heart defects.
- name: Hypospadias
  category: Genitourinary
  description: >-
    Affected males present with genital malformations - most commonly
    hypospadias - in place of the female hydrometrocolpos.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genital malformations in males (most commonly hypospadias, cryptorchidism,
      and chordee)
    explanation: >-
      Hypospadias is one of the characteristic male genital malformations of MKS.
- name: Cryptorchidism
  category: Genitourinary
  description: >-
    Cryptorchidism (undescended testes) is among the male genital malformations
    seen in McKusick-Kaufman syndrome.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genital malformations in males (most commonly hypospadias, cryptorchidism,
      and chordee)
    explanation: >-
      Cryptorchidism is one of the characteristic male genital malformations of MKS.
- name: Chordee
  category: Genitourinary
  description: >-
    Chordee (ventral penile curvature) is among the male genital malformations
    seen in McKusick-Kaufman syndrome.
  phenotype_term:
    preferred_term: Chordee
    term:
      id: HP:0000041
      label: Chordee
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genital malformations in males (most commonly hypospadias, cryptorchidism,
      and chordee)
    explanation: >-
      Chordee is one of the characteristic male genital malformations of MKS.
discussions:
- discussion_id: gap_mkks_genotype_phenotype_mks_vs_bbs
  prompt: >-
    Can MKKS/BBS6 genotype predict whether a patient will manifest the
    McKusick-Kaufman-restricted phenotype (limb + genitourinary) versus
    full Bardet-Biedl syndrome, and can the two be distinguished in the
    neonatal period?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#MKKS chaperonin assembly defect
  - pathophysiology#BBSome-dependent ciliary cargo trafficking failure
  rationale: >-
    The Mkks-null mouse supports a mechanistic model in which complete loss of
    function produces Bardet-Biedl syndrome while specific (hypomorphic) missense
    alleles produce the McKusick-Kaufman-restricted phenotype. At the human
    clinical level, however, no reliable genotype-phenotype correlation has been
    established and the McKusick-Kaufman triad cannot be reliably differentiated
    from neonatal Bardet-Biedl syndrome, so an early McKusick-Kaufman diagnosis
    may be reclassified as Bardet-Biedl syndrome on follow-up. Whether allele
    type, modifiers, or oligogenic load resolve this is unresolved.
  evidence:
  - reference: PMID:15772095
    reference_title: "Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These observations suggest that the complete absence of MKKS leads to BBS
      while the MKS phenotype is likely to be due to specific mutations.
    explanation: >-
      Provides the model-organism basis for the null-vs-missense allelic
      hypothesis while leaving the human genotype-phenotype prediction open.
  - reference: PMID:22090721
    reference_title: "McKusick-Kaufman or Bardet-Biedl syndrome? A new borderline case in an Italian nonconsanguineous healthy family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HMC, CHD, and PAP defects can also occur in BBS-6, and there is a
      significant clinical overlap between MKS and BBS-6 in childhood.
    explanation: >-
      Documents the significant childhood clinical overlap that prevents
      reliable early differentiation of McKusick-Kaufman from Bardet-Biedl.
  - reference: PMID:26900326
    reference_title: "A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our observations reaffirm the notion that mutations in MKKS/BBS6 cause
      phenotypic heterogeneity and do not always result in classic MKKS or BBS
      findings.
    explanation: >-
      An MKKS/BBS6 allele producing only RP and polydactyly demonstrates that the
      MKKS allelic series is a continuum without a clean genotype-phenotype
      boundary between McKusick-Kaufman and Bardet-Biedl.
- discussion_id: mismatch_mkks_noncilliary_chd_human_fidelity
  prompt: >-
    Does the non-ciliary BBS6 nuclear-cytoplasmic transport / SMARCC1
    chromatin-remodeling defect actually drive congenital heart disease in human
    McKusick-Kaufman syndrome patients, as it does in the zebrafish and cell
    models?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Non-ciliary BBS6 nuclear-cytoplasmic transport defect
  - phenotype#Congenital heart disease
  rationale: >-
    The nuclear-cytoplasmic transport / SMARCC1 mechanism for MKS congenital
    heart disease is demonstrated in zebrafish and in cell-based assays of the
    MKS-associated BBS6 H84Y;A242S allele, but its fidelity to human cardiac
    morphogenesis is not yet established. This is a HUMAN_MODEL_MISMATCH rather
    than a generic knowledge gap: a specific non-ciliary mechanism exists in
    model systems, and the open question is its translational validity to the
    human heart defect.
  proposed_experiments:
  - experiment_id: exp_mkks_chd_human_cardiac_tissue
    name: Test the BBS6 nuclear-transport/SMARCC1 axis in human cardiac models
    description: >-
      Use patient-derived or genome-edited human iPSC-cardiomyocytes / cardiac
      organoids carrying the MKS BBS6 H84Y;A242S allele to test whether
      BBS6 nuclear-cytoplasmic transport and SMARCC1-dependent chromatin
      remodeling are perturbed and whether cardiac differentiation/morphogenesis
      is affected, establishing or refuting human relevance of the model-system
      mechanism.
  evidence:
  - reference: PMID:28753627
    reference_title: "Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our work identifies a new function for BBS6 in nuclear-cytoplasmic
      transport, and provides insight into the disease mechanism underlying the
      congenital heart defects in McKusick-Kaufman syndrome patients
    explanation: >-
      Provides the model-system mechanism whose human cardiac fidelity is the
      open question.
prevalence:
- population: General (outside founder populations)
  percentage: Rare
  notes: >-
    McKusick-Kaufman syndrome is rare; it was originally mapped in the Old Order
    Amish population and is otherwise reported mostly as isolated cases, with
    diagnosis complicated by clinical overlap with Bardet-Biedl syndrome.
  evidence:
  - reference: PMID:35860126
    reference_title: "A case of McKusick-Kaufman syndrome with perinatal diagnosis: Case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      McKusick-Kaufman syndrome (MKS) is a rarely reported autosomal recessive
      syndrome characterized by hydrometrocolpos (HMC), polydactyly and various
      gastrointestinal and renal manifestations
    explanation: >-
      Confirms the rarity of MKS and its cardinal hydrometrocolpos/polydactyly
      features.
diagnosis:
- name: Clinical and molecular diagnosis
  description: >-
    McKusick-Kaufman syndrome is suspected from the combination of
    hydrometrocolpos and postaxial polydactyly (with or without congenital heart
    disease) and confirmed by biallelic MKKS pathogenic variants on molecular
    genetic testing. Because the age-dependent features of Bardet-Biedl syndrome
    may not yet be apparent, Bardet-Biedl syndrome must be excluded before
    committing to a diagnosis of McKusick-Kaufman syndrome, particularly before
    age 5.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic pathogenic variants in MKKS identified by molecular genetic
      testing
    explanation: >-
      Defines the molecular diagnostic criterion (biallelic MKKS variants) for
      McKusick-Kaufman syndrome.
differential_diagnoses:
- name: Bardet-Biedl syndrome
  description: >-
    Bardet-Biedl syndrome is the allelic (MKKS/BBS6) condition with the greatest
    overlap: it shares hydrometrocolpos and polydactyly but is distinguished by
    age-dependent retinal dystrophy, obesity, and intellectual disability, which
    may be absent in infancy - so the two can be clinically indistinguishable in
    the neonatal period.
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an allelic condition with considerable clinical overlap and age-dependent
      features including retinal dystrophy, obesity, and intellectual disability
    explanation: >-
      Establishes Bardet-Biedl syndrome as the principal allelic differential,
      distinguished by age-dependent retinal/metabolic features.
  - reference: PMID:35860126
    reference_title: "A case of McKusick-Kaufman syndrome with perinatal diagnosis: Case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      retinal manifestations are a differentiating feature from MKS
    explanation: >-
      Confirms retinal involvement as the key feature distinguishing
      Bardet-Biedl syndrome from McKusick-Kaufman syndrome.
treatments:
- name: Surgical correction of hydrometrocolpos and malformations
  description: >-
    Management is directed at the structural anomalies: surgical repair of the
    obstruction causing hydrometrocolpos with drainage of accumulated fluid, and
    standard treatment of polydactyly and congenital heart defects. Care is
    needed with anesthesia in the neonatal period because severe hydrometrocolpos
    can cause diaphragmatic compression.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of the obstruction causing HMC and drainage of the
      accumulated fluid
    explanation: >-
      Defines the standard surgical management of hydrometrocolpos in MKS.
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Care with anesthesia in the neonatal period as severe HMC can cause
      diaphragmatic compression
    explanation: >-
      GeneReviews agents/circumstances-to-avoid caution: neonatal anesthesia risk
      from hydrometrocolpos-related diaphragmatic compression.
- name: Supportive and multidisciplinary care
  description: >-
    Care is supportive and multidisciplinary, with surveillance for later
    complications of hydrometrocolpos surgery and ongoing monitoring for emerging
    Bardet-Biedl syndrome features (vision, growth, renal, and developmental
    assessments).
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ongoing surveillance for manifestations of BBS including growth and
      developmental assessments, ophthalmologic examination, and electroretinogram
    explanation: >-
      Supports surveillance for emerging Bardet-Biedl syndrome features in
      individuals diagnosed with McKusick-Kaufman syndrome.
- name: Genetic counseling
  description: >-
    Autosomal recessive inheritance entails a 25% recurrence risk for siblings;
    once biallelic MKKS variants are identified, carrier, prenatal, and
    preimplantation genetic testing become available. Counseling should note that
    an apparent McKusick-Kaufman diagnosis may later prove to be Bardet-Biedl
    syndrome.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301675
    reference_title: "McKusick-Kaufman Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being
      affected
    explanation: >-
      States the 25% sibling recurrence risk underpinning genetic counseling.
references:
- reference: PMID:20301675
  title: "McKusick-Kaufman Syndrome."
  tags:
  - GeneReviews
- reference: PMID:10802661
  title: "Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome."
- reference: PMID:28753627
  title: "Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein."
- reference: PMID:15731008
  title: "MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis."
- reference: PMID:18094050
  title: "MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination."
📚

References & Deep Research

References

5
PMID:20301675
McKusick-Kaufman Syndrome.
No top-level findings curated for this source.
PMID:10802661
Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome.
No top-level findings curated for this source.
PMID:28753627
Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein.
No top-level findings curated for this source.
PMID:15731008
MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis.
No top-level findings curated for this source.
PMID:18094050
MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination.
No top-level findings curated for this source.