RECON (RECql ONe) syndrome is an autosomal recessive genome instability disorder with a progeroid facial gestalt, caused by biallelic variants in RECQL (RECQL1), the RecQ-family 3'-5' DNA helicase that had no associated human disease before 2022. The entire published cohort is three girls from two Middle Eastern families (one consanguineous), all homozygous for the same zinc-binding-domain missense variant, p.Ala459Ser, and all evaluated in childhood (4 to 14 years). Growth deficiency is postnatal: birth weights at term were normal, while height and especially weight fell below the mean, most severely in the one child followed into adolescence. Cutaneous photosensitivity, xeroderma, a progeroid face with a tiny pinched (hypoplastic) nose and prominent premaxilla, and slender elongated thumbs were present in all three; reduced subcutaneous fat, dry eyes, red eyes and hirsutism were seen in some. Developmental milestones were age appropriate in all three. The variant is hypomorphic: the mutant protein is expressed and localizes normally but has reduced ATPase, helicase and reversed-fork restoration activity with preserved strand annealing, and patient cells show spontaneous replication fork stalling, defective fork restart, impaired repair of topoisomerase-poison-induced breaks and increased chromosome breakage. How this cellular defect produces the clinical features is not established. No cancers have been reported in affected individuals or their heterozygous relatives, but the cohort is too small and young to assess cancer risk or adult natural history, and no disease-specific management or surveillance has been published.
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Conditions with similar clinical presentations that must be differentiated from RECON Progeroid Syndrome:
name: RECON Progeroid Syndrome
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
description: >-
RECON (RECql ONe) syndrome is an autosomal recessive genome instability
disorder with a progeroid facial gestalt, caused by biallelic variants in
RECQL (RECQL1), the RecQ-family 3'-5' DNA helicase that had no associated
human disease before 2022. The entire published cohort is three girls from
two Middle Eastern families (one consanguineous), all homozygous for the same
zinc-binding-domain missense variant, p.Ala459Ser, and all evaluated in
childhood (4 to 14 years). Growth deficiency is postnatal: birth weights at
term were normal, while height and especially weight fell below the mean,
most severely in the one child followed into adolescence. Cutaneous
photosensitivity, xeroderma, a progeroid face with a tiny pinched
(hypoplastic) nose and prominent premaxilla, and slender elongated thumbs
were present in all three; reduced subcutaneous fat, dry eyes, red eyes and
hirsutism were seen in some. Developmental milestones were age appropriate in
all three. The variant is hypomorphic: the mutant protein is expressed and
localizes normally but has reduced ATPase, helicase and reversed-fork
restoration activity with preserved strand annealing, and patient cells show
spontaneous replication fork stalling, defective fork restart, impaired
repair of topoisomerase-poison-induced breaks and increased chromosome
breakage. How this cellular defect produces the clinical features is not
established. No cancers have been reported in affected individuals or their
heterozygous relatives, but the cohort is too small and young to assess
cancer risk or adult natural history, and no disease-specific management or
surveillance has been published.
parents:
- Genetic Disease
synonyms:
- RECON syndrome
- RECQL1-related progeroid syndrome
notes: >-
Lump/split. This entry covers only the biallelic (autosomal recessive)
progeroid disorder. Heterozygous RECQL loss-of-function variants have been
proposed as a moderate-penetrance breast cancer susceptibility factor; that
is a separate, contested gene-disease claim (ClinGen Hereditary Cancer GCEP
classifies RECQL with hereditary breast carcinoma, autosomal dominant, as
Disputed, assertion CGGV:assertion_777b2a5c-459f-4eee-8a6d-e8bf15b88aca,
2023-03-13) and is recorded here only as a discussion attached to the gene,
never as a phenotype of RECON syndrome. Gene-disease validity for RECQL with
RECON progeroid syndrome itself has no ClinGen curation; in the GenCC
submissions export (downloaded 2026-09-23) it is classified Limited by Labcorp
Genetics (2023-07-13) and Moderate by PanelApp Australia (2025-01-17). No
Orphanet disorder record for RECON syndrome was found in the Orphadata
en_product1.xml release pinned in data/orphadata/MANIFEST.yaml (search for
"RECON" and "RECQL" returned no match). No GeneReviews chapter exists. All
phenotype data derive from one primary report of three individuals
(PMID:35025765); frequencies are given as counts only where a source states
the denominator. Developmental milestones were age appropriate in each of
the three. No treatment, surveillance protocol, or clinical trial has been
published, so the entry has no treatments section.
disease_term:
preferred_term: RECON progeroid syndrome
term:
id: MONDO:0957266
label: RECON progeroid syndrome
mappings:
mondo_mappings:
- term:
id: MONDO:0957266
label: RECON progeroid syndrome
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO disease identifier for this entry.
external_assertions:
- name: OMIM RECON progeroid syndrome
source: OMIM
assertion_type: disease_record
external_id: OMIM:620370
description: >-
OMIM phenotype entry for RECON progeroid syndrome, listed as a database
cross-reference on MONDO:0957266.
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene"
explanation: >-
A single-gene inherited genome instability disorder, classified under
genetics.
prevalence:
- population: Worldwide (published case reports)
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Three genotyped affected individuals from two families, all homozygous for
RECQL p.Ala459Ser. Two adult first cousins of the family A parents were
reported to have similar features but were not genotyped or examined.
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "only 3 affected individuals have been identified, all with the same mutation"
explanation: >-
The 2023 perspective by the discovering group states the total published
cohort size.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The family history was also positive for 2 common adult first cousins of the parents who had similar clinical features. Unfortunately, these relatives were not available for genetic evaluation or a detailed medical workup."
explanation: >-
Two further, ungenotyped relatives with similar features are reported
but are not counted as confirmed cases.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
All three affected individuals were homozygous for RECQL p.Ala459Ser,
while available parents and eight unaffected siblings were heterozygous or
wild type. Family A parents were double first cousins; family B reported no
known consanguinity. No recurrence-risk figure has been published for this
disease specifically.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All 3 affected individuals (III-2 and III-4 from family A and III-4 from family B) were homozygous for this variant, whereas the available parents and 8 healthy siblings were either heterozygous or WT"
explanation: >-
Segregation of the homozygous genotype with disease, with unaffected
heterozygous relatives, supports recessive inheritance.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She was the second of 5 children born to parents of Middle Eastern descent, who were double first cousins"
explanation: Parental consanguinity in family A.
genetic:
- name: RECQL
association: Biallelic hypomorphic missense (homozygous p.Ala459Ser)
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: RECQL
term:
id: hgnc:9948
label: RECQL
notes: >-
Only one disease-causing allele is known, NM_032941.2:c.1375G>T
p.(Ala459Ser), in the zinc-binding domain, found homozygous in two families
not known to be related. It is absent from gnomAD and the Greater Middle
East variome. Whether null or other RECQL alleles produce the same or a
more severe phenotype is unknown.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1"
explanation: Gene discovery report of the homozygous RECQL variant in affected individuals.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this variant is not found in the gnomAD or Greater Middle East (GME) variome databases"
explanation: Absence from population databases supports a rare pathogenic allele.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these individuals are not null for RECQL1 and that the severity of the resulting clinical symptoms is likely to be tempered by the presence of some residual protein function"
explanation: >-
The authors characterize the allele as hypomorphic and caution that the
phenotype of null alleles is unknown.
pathophysiology:
- name: RECQL1 Zinc-Binding Domain Hypomorphic Missense Variant
description: >-
Homozygous germline RECQL c.1375G>T p.(Ala459Ser) substitutes a conserved
alanine in the RECQL1 zinc-binding domain. Mutant protein is expressed at
normal levels in patient lymphoblastoid cells, localizes to the nucleus and
still associates with PARP1, so the defect is catalytic rather than a loss
of protein.
biological_scale: MOLECULAR
genes:
- preferred_term: RECQL
term:
id: hgnc:9948
label: RECQL
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
variant_type: single nucleotide variant
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
gene:
preferred_term: RECQL
term:
id: hgnc:9948
label: RECQL
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain"
explanation: Identifies the causal variant and its domain location.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed no obvious differences in the expression of RECQL1 protein in LCLs from the 2 affected patients when compared with the expression of RECQL1 in LCLs from 2 normal individuals"
explanation: Mutant protein is stably expressed in patient cells.
downstream:
- target: Reduced RECQL1 ATPase and Helicase Activity
causal_link_type: DIRECT
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected."
explanation: Recombinant mutant protein assays link the variant to the catalytic defect.
- name: Reduced RECQL1 ATPase and Helicase Activity
description: >-
Recombinant RECQL1-A459S has reduced ATP turnover, reduced unwinding of
forked duplexes and reduced restoration of reversed replication forks,
with modestly reduced DNA binding. Single-strand annealing and
oligomerization are preserved, so the variant selectively impairs the
ATP-driven motor function.
biological_scale: MOLECULAR
genes:
- preferred_term: RECQL
term:
id: hgnc:9948
label: RECQL
molecular_functions:
- preferred_term: DNA helicase activity
modifier: DECREASED
term:
id: GO:0003678
label: DNA helicase activity
- preferred_term: ATP hydrolysis activity
modifier: DECREASED
term:
id: GO:0016887
label: ATP hydrolysis activity
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "At a protein concentration of 2.5 nM, WT RECQL1 unwound nearly 60% of the DNA substrate compared with approximately 20% for mutant RECQL1"
explanation: Quantifies the helicase deficit of the mutant protein.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "WT RECQL1 had a nearly 3-fold higher kcat for ATP hydrolysis in the presence of the M13mp18 ssDNA effector compared with RECQL1-A459S"
explanation: Quantifies the ATPase deficit of the mutant protein.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the strand annealing activity of WT and mutant RECQL1 proteins was nearly identical over a range of protein concentrations"
explanation: Strand annealing is preserved, so the loss of function is partial and selective.
downstream:
- target: Defective Replication Fork Restart
causal_link_type: DIRECT
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the p.A459S mutant RECQL1 consistently had a reduced ability to restore the replication fork compared with WT RECQL1"
explanation: >-
In a reconstituted reversed-fork assay the catalytic defect directly
reduces fork restoration, the biochemical step underlying restart.
- target: Stalled Replication Fork Degradation
- target: Impaired Repair of Topoisomerase-Associated DNA Breaks
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions."
explanation: Links the variant to the repair defect in patient-derived cells.
- name: Stalled Replication Fork Degradation
description: >-
Patient fibroblasts expressing empty vector or RECQL1-A459S show a mild
increase in nascent-strand degradation after prolonged hydroxyurea
exposure, corrected by wild-type RECQL1. The authors attribute the
fork-restart defect partly to this degradation.
biological_scale: CELLULAR
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "RECQL-P1-1 fibroblasts complemented with empty vector and the p.A459S exhibited a mild increase in replication fork degradation after prolonged exposure to HU that could be complemented following the expression of WT RECQL1"
explanation: Fiber-assay evidence of increased fork degradation, rescued by wild-type protein.
downstream:
- target: Defective Replication Fork Restart
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the replication fork restart defect present in the cells derived from patients with RECON syndrome was not only due to an inability of the mutant RECQL1 to remodel reversed forks but also resulted from the degradation of stalled forks"
explanation: The authors attribute part of the restart defect to fork degradation.
- name: Defective Replication Fork Restart
description: >-
Patient lymphoblastoid cells show more spontaneously stalled forks
(endogenous replication stress), and patient cells fail to restart forks
stalled by topoisomerase I or II poisons, hydroxyurea or MMS. Fork speed
and origin firing are grossly normal before treatment. The defects are
corrected by wild-type but not A459S RECQL1.
biological_scale: CELLULAR
genes:
- preferred_term: RECQL
term:
id: hgnc:9948
label: RECQL
biological_processes:
- preferred_term: replication fork restart
modifier: DECREASED
term:
id: GO:0031297
label: replication fork processing
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "even in the absence of exposure to genotoxins, both RECQL1 LCLs had an increase in spontaneously stalled forks indicative of higher levels of endogenous replication stress"
explanation: Spontaneous replication stress in patient cells.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "these data suggest that the clinically relevant p.A459S mutation in the RECQL1 ZBD, which perturbs its catalytic activity, compromises the ability of RECQL1 to restart reversed replication forks."
explanation: Fiber analysis in patient LCLs and complemented fibroblasts shows the restart defect.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the p.A459S mutation significantly compromised the ability of replication forks transiently stalled by HU to restart efficiently"
explanation: The restart defect extends beyond topoisomerase lesions to nucleotide-depletion stalling.
downstream:
- target: Chromosomal Instability
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the p.A459S mutant also compromised the ability of cells to restart replication in the presence of DNA alkylation damage induced by MMS exposure, accompanied by increased chromosome breakage and cell death"
explanation: >-
The restart failure is accompanied by increased chromosome breakage in
the same cells; this is co-occurrence in one experiment rather than a
dissected causal step.
- name: Impaired Repair of Topoisomerase-Associated DNA Breaks
description: >-
Patient fibroblasts lacking functional RECQL1 retain more 53BP1 foci for 24
hours after camptothecin or etoposide and have more spontaneous foci.
ATM-dependent damage signaling is robustly activated in patient cells, so
the defect lies in repair or replication through the lesion rather than in
damage sensing. Breakage and translocation at the MLL locus after
etoposide, the signature of TDP2 deficiency, was not increased.
biological_scale: CELLULAR
conforms_to: "genomic_instability_aging#Declining Genome Maintenance and Erroneous Repair"
biological_processes:
- preferred_term: double-strand break repair
modifier: DECREASED
term:
id: GO:0006302
label: double-strand break repair
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "patients’ cells expressing either the empty vector or the p.A459S-mutant RECQL1 had higher numbers of 53BP1 foci in cells throughout a 24-hour time course following exposure to CPT or ETOP than did cells expressing WT RECQL1"
explanation: Persistent 53BP1 foci indicate slower repair of topoisomerase-poison-induced breaks.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "both RECQL1-mutant cell lines showed robust activation of the ATM-dependent DDR"
explanation: Damage signaling is intact, localizing the defect downstream of sensing.
downstream:
- target: Chromosomal Instability
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "cells containing the empty vector or expressing p.A459S-mutant RECQL1 exhibited significantly greater numbers of spontaneous and CPT- or ETOP-induced micronuclei than did their WT RECQL1–expressing counterparts"
explanation: Unrepaired breaks manifest as micronuclei, a marker of genome instability.
- name: Chromosomal Instability
description: >-
Patient lymphoblastoid cells and fibroblasts show increased spontaneous
and camptothecin- or etoposide-induced chromosome breakage and radial
exchanges, more micronuclei, and a mild increase in sister chromatid
exchange; the breakage is corrected by wild-type RECQL1. Constitutional
karyotype and diepoxybutane-induced breakage were normal in family B, so
this is a cellular, not a karyotypic, finding. Its link to the clinical
features has not been demonstrated.
biological_scale: CELLULAR
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the RECQL1-P1-1 and RECQL1-P2 LCLs had higher levels of spontaneous and CPT- or ETOP-induced chromosome breakage than did 2 normal LCLs"
explanation: Increased chromosome breakage in both patients' cell lines.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "both the increased spontaneous and CPT- or ETOP-induced chromosome breakages were also observed in fibroblasts from patient RECQL1-P1 and could be complemented by the expression of exogenous WT but not mutant A459S RECQL1"
explanation: Complementation ties the breakage phenotype to RECQL1 dysfunction.
downstream:
- target: Chromosome Breakage
- target: Increased Sister Chromatid Exchange
phenotypes:
- category: Growth
name: Short Stature
description: >-
Postnatal. Birth weights at term were about 3000 g and 3500 g. Height
z-scores were -1.98 (9 years 8 months) and -1.02 (4 years) in the family A
sisters; the family B proband went from -0.7 at 5 years 10 months to -3.59
at 14 years 9 months. The discovering authors list postnatal growth
retardation as the only feature shared with Bloom and RECQL4-related
syndromes.
phenotype_term:
preferred_term: Postnatal short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity"
explanation: Short stature is a cardinal reported feature.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Follow-up measurements at age 14 years, 9 months revealed a height of 138.4 cm (z score, -3.59), a weight of 22.1 kg (z score, -8.47), and a head circumference of 50.8 cm (z score, -2.92)"
explanation: Worsening height deficit on adolescent follow-up of the family B proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband was born at term with a birth weight of approximately 3000 grams."
explanation: Normal term birth weight indicates the growth deficiency is postnatal.
- category: Growth
name: Low Body Weight
description: >-
Weight z-scores were -2.05 and -1.05 in the family A sisters and -3.4 at 5
years 10 months falling to -8.47 at 14 years 9 months in the family B
proband, disproportionately worse than height.
phenotype_term:
preferred_term: Decreased body weight
term:
id: HP:0004325
label: Decreased body weight
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Follow-up measurements at age 14 years, 9 months revealed a height of 138.4 cm (z score, -3.59), a weight of 22.1 kg (z score, -8.47)"
explanation: Severe weight deficit in adolescence in the family B proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "height of 123.8 cm (z score, -1.98), a weight of 22.5 kg (z score, -2.05)"
explanation: Low weight in the family A proband at 9 years 8 months.
- category: Growth
name: Reduced Subcutaneous Fat
description: >-
Little subcutaneous fat in the younger family A sister; thin extremities
with hypoplastic subcutaneous fat in the family B proband.
phenotype_term:
preferred_term: Reduced subcutaneous adipose tissue
term:
id: HP:0003758
label: Reduced subcutaneous adipose tissue
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had dysmorphism including a somewhat aged (progeroid) appearance with little subcutaneous fat"
explanation: Reduced subcutaneous fat in the younger family A sister.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband had thin extremities with hypoplastic muscles and subcutaneous fat."
explanation: Reduced subcutaneous fat in the family B proband.
- category: Musculoskeletal
name: Reduced Muscle Mass
description: >-
Hypoplastic limb muscles in the family B proband; the authors describe
muscle wasting as reminiscent of Werner syndrome.
phenotype_term:
preferred_term: Hypoplastic muscles
term:
id: HP:0003199
label: Decreased muscle mass
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband had thin extremities with hypoplastic muscles and subcutaneous fat."
explanation: Reduced muscle bulk in the family B proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the progeroid-like facial appearance, growth retardation, and muscle wasting are somewhat reminiscent of WS"
explanation: The authors list muscle wasting among the Werner-like features.
- category: Craniofacial
name: Progeroid Facial Appearance
description: >-
An aged, mask-like facial appearance with little subcutaneous fat, present
by early childhood in all three affected individuals.
frequency: 3/3
diagnostic: true
phenotype_term:
preferred_term: Progeroid facial appearance
term:
id: HP:0005328
label: Progeroid facial appearance
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All three probands of ages 9 yr 8 mo, 4 yr, 0 mo, and 14 yr, 9 mo at time of evaluation displayed photosensitivity, xeroderma, characteristic progeroid facial features, and slender elongated thumbs accompanied by other skeletal abnormalities."
explanation: States the feature was present in all three individuals (3/3).
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It appears that the defining clinical features of RECON syndrome include skin photosensitivity, xeroderma, and a progeroid-like facial appearance with a tiny, pinched nose and prominent premaxilla."
explanation: The discovering authors name the progeroid face as a defining feature.
- category: Craniofacial
name: Hypoplastic Nose
description: >-
A tiny, pinched nose described in all three individuals, with hypoplastic
alae nasi in the family B proband. In the family A proband the small nose
was the reason medical evaluation was first sought, at 18 months.
diagnostic: true
phenotype_term:
preferred_term: Hypoplastic, tiny pinched nose
term:
id: HP:0003196
label: Short nose
onset:
onset_category: INFANTILE
max_age_years: 1.5
notes: Noted by 18 months in the family A proband; earlier onset not documented.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 18 months of age, medical evaluation was sought, since her nose remained exceptionally small compared with the rest of her face"
explanation: Nasal hypoplasia evident by 18 months.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a prominent nasal bridge with a tiny, pinched nose with hypoplastic alae nasi"
explanation: Same feature in the family B proband.
- category: Craniofacial
name: Anteverted Nares
description: Anteverted nares in both family A sisters.
phenotype_term:
preferred_term: Anteverted nares
term:
id: HP:0000463
label: Anteverted nares
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a tiny, pinched nose with anteverted nares, prominent premaxilla, and a smooth philtrum"
explanation: Reported in the family A sisters' facial description.
- category: Craniofacial
name: Prominent Premaxilla
description: Reported in all three individuals.
phenotype_term:
preferred_term: Prominent premaxilla
term:
id: HP:0010759
label: Prominence of the premaxilla
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband’s dysmorphic features included a round face, redness of eyes, a tiny, pinched nose with anteverted nares, prominent premaxilla, and a smooth philtrum"
explanation: Prominent premaxilla in the family A proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a prominent nasal bridge with a tiny, pinched nose with hypoplastic alae nasi, prominent premaxilla, thin lips, and a smooth philtrum"
explanation: Prominent premaxilla in the family B proband.
- category: Craniofacial
name: Smooth Philtrum
description: Reported in all three individuals.
phenotype_term:
preferred_term: Smooth philtrum
term:
id: HP:0000319
label: Smooth philtrum
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband’s dysmorphic features included a round face, redness of eyes, a tiny, pinched nose with anteverted nares, prominent premaxilla, and a smooth philtrum"
explanation: Smooth philtrum in the family A proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a prominent nasal bridge with a tiny, pinched nose with hypoplastic alae nasi, prominent premaxilla, thin lips, and a smooth philtrum"
explanation: Smooth philtrum in the family B proband.
- category: Craniofacial
name: Round Face
description: Reported in the family A proband.
phenotype_term:
preferred_term: Round face
term:
id: HP:0000311
label: Round face
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband’s dysmorphic features included a round face"
explanation: Round face in the family A proband.
- category: Craniofacial
name: Thin Lips
description: Reported in the family B proband.
phenotype_term:
preferred_term: Thin lips
term:
id: HP:0000233
label: Thin vermilion border
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "prominent premaxilla, thin lips, and a smooth philtrum"
explanation: Thin lips in the family B proband.
- category: Craniofacial
name: Small Attached Earlobes
description: Small ears with small, attached earlobes in the family B proband.
phenotype_term:
preferred_term: Small, attached earlobes
term:
id: HP:0000385
label: Small earlobe
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "small ears with small, attached earlobes"
explanation: Ear finding in the family B proband.
- category: Ocular
name: Deeply Set Eyes
description: Reported in the family B proband.
phenotype_term:
preferred_term: Deep-set eyes
term:
id: HP:0000490
label: Deeply set eye
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dysmorphic features included a mask senile-like face (progeroid), deep-set eyes, absent lower lid eyelashes"
explanation: Deep-set eyes in the family B proband.
- category: Ocular
name: Absent Lower Eyelid Eyelashes
description: Reported in the family B proband; upper lashes not described as affected.
phenotype_term:
preferred_term: Absent lower eyelid eyelashes
term:
id: HP:0000561
label: Absent eyelashes
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "deep-set eyes, absent lower lid eyelashes"
explanation: Absent lower lashes in the family B proband.
- category: Ocular
name: Dry Eyes
description: >-
Xerophthalmia in the family A proband, present at the 18-month
evaluation. Not described in the other two individuals.
phenotype_term:
preferred_term: Xerophthalmia (dry eyes)
term:
id: HP:0001097
label: Keratoconjunctivitis sicca
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "her eyes remained open while sleeping, and she had xerophthalmia (dry eyes) and xeroderma (dry skin) with scaling"
explanation: Dry eyes in the family A proband by 18 months.
- category: Ocular
name: Nocturnal Lagophthalmos
description: Eyes remained open during sleep in the family A proband at 18 months.
phenotype_term:
preferred_term: Eyes remain open during sleep
term:
id: HP:0030002
label: Nocturnal lagophthalmos
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "her eyes remained open while sleeping"
explanation: Incomplete eyelid closure during sleep in the family A proband.
- category: Ocular
name: Red Eyes
description: Redness of the eyes in both family A sisters.
phenotype_term:
preferred_term: Red eyes
term:
id: HP:0030953
label: Conjunctival hyperemia
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "somewhat aged (progeroid) appearance with little subcutaneous fat, red eyes"
explanation: Red eyes in the younger family A sister.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband’s dysmorphic features included a round face, redness of eyes"
explanation: Red eyes in the family A proband.
- category: Dermatological
name: Xeroderma
description: >-
Dry, scaling skin, noted by 18 months in the family A proband; in the
family B proband thin, dry skin with desquamation mainly on sun-exposed
areas.
frequency: 3/3
diagnostic: true
phenotype_term:
preferred_term: Xeroderma
term:
id: HP:0000958
label: Dry skin
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All three probands of ages 9 yr 8 mo, 4 yr, 0 mo, and 14 yr, 9 mo at time of evaluation displayed photosensitivity, xeroderma, characteristic progeroid facial features, and slender elongated thumbs"
explanation: States the feature was present in all three individuals (3/3).
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we observed thin, dry skin (xeroderma) with areas of desquamation (scaling), mainly on exposed body parts, suggestive of photosensitivity"
explanation: Clinical description in the family B proband.
- category: Dermatological
name: Cutaneous Photosensitivity
description: >-
Parent-reported in both families and suggested on examination by scaling
confined mainly to sun-exposed skin. No phototesting or description of
the skin reaction to sun has been published.
frequency: 3/3
diagnostic: true
phenotype_term:
preferred_term: Cutaneous photosensitivity
term:
id: HP:0000992
label: Cutaneous photosensitivity
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All three probands of ages 9 yr 8 mo, 4 yr, 0 mo, and 14 yr, 9 mo at time of evaluation displayed photosensitivity"
explanation: States the feature was present in all three individuals (3/3).
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The parents reported that their child had photosensitivity."
explanation: Parent report in family A.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The parents reported that their child was photosensitive."
explanation: Parent report in family B.
- category: Dermatological
name: Livedo Reticularis
description: Reported in the family A proband.
phenotype_term:
preferred_term: Livedo reticularis
term:
id: HP:0033505
label: Livedo reticularis
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband also had livedo reticularis and keratosis pilaris"
explanation: Skin finding in the family A proband.
- category: Dermatological
name: Keratosis Pilaris
description: Reported in the family A proband.
phenotype_term:
preferred_term: Keratosis pilaris
term:
id: HP:0032152
label: Keratosis pilaris
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband also had livedo reticularis and keratosis pilaris"
explanation: Skin finding in the family A proband.
- category: Dermatological
name: Localized Hirsutism
description: Hirsutism of the back in the younger family A sister and of the lower limbs in the family B proband.
phenotype_term:
preferred_term: Hirsutism of the back or lower limbs
term:
id: HP:0009889
label: Localized hirsutism
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "she had mild hirsutism of the back"
explanation: Back hirsutism in the younger family A sister.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had hirsutism of the lower limbs"
explanation: Lower-limb hirsutism in the family B proband.
- category: Musculoskeletal
name: Long Slender Thumbs
description: >-
Slender, elongated thumbs in all three individuals, proximally inserted in
the younger family A sister. The discovering authors distinguish this from
the absent or hypoplastic thumbs of RECQL4-related disorders.
frequency: 3/3
diagnostic: true
phenotype_term:
preferred_term: Slender, elongated thumbs
term:
id: HP:0032524
label: Long thumb
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "characteristic progeroid facial features, and slender elongated thumbs accompanied by other skeletal abnormalities"
explanation: States slender elongated thumbs in all three probands (3/3; same sentence begins "All three probands").
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her thumbs were long and slender with proximal insertion"
explanation: Thumb finding in the younger family A sister.
- category: Musculoskeletal
name: Hyperconvex Thumb Nails
description: Hyperconvex thumb nails in the family A proband and the family B proband.
phenotype_term:
preferred_term: Hyperconvex thumb nails
term:
id: HP:0008407
label: Hyperconvex thumb nails
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her thumbs were slender and elongated, with hyperconvex nails."
explanation: Family A proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "her thumbs were slender and elongated, with hyperconvex nails"
explanation: Family B proband.
- category: Musculoskeletal
name: Arachnodactyly
description: Bilateral arachnodactyly in the family B proband.
phenotype_term:
preferred_term: Arachnodactyly
term:
id: HP:0001166
label: Arachnodactyly
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband had bilateral arachnodactyly"
explanation: Family B proband.
- category: Musculoskeletal
name: Joint Hypermobility
description: >-
Mild: slight elbow hyperextension without finger laxity in the family A
proband, and minor finger joint laxity in her younger sister.
phenotype_term:
preferred_term: Mild joint hypermobility
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had slight hyperextension of the elbows but no joint laxity in the fingers."
explanation: Family A proband.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We noted minor joint laxity of the fingers"
explanation: Younger family A sister.
- category: Dental
name: Delayed Eruption of Permanent Teeth
description: Primary teeth erupted normally; permanent teeth were delayed in the family A proband.
phenotype_term:
preferred_term: Delayed eruption of permanent teeth
term:
id: HP:0000696
label: Delayed eruption of permanent teeth
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "however, eruption of her permanent teeth was delayed"
explanation: Family A proband.
- category: Growth
name: Decreased Head Circumference
description: >-
Head circumference z-scores were -1.64 and -1.18 in the family A sisters
and -2.9 at 5 years 10 months and -2.92 at 14 years 9 months in the family
B proband. The discovering authors nonetheless cite microcephaly as a
feature that distinguishes Bloom syndrome from RECON syndrome, so a reduced
head circumference should not be read as defining microcephaly here.
phenotype_term:
preferred_term: Decreased head circumference
term:
id: HP:0040195
label: Decreased head circumference
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a weight of 22.1 kg (z score, -8.47), and a head circumference of 50.8 cm (z score, -2.92)"
explanation: Head circumference below -2 SD in the family B proband at 14 years 9 months.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a weight of 22.5 kg (z score, -2.05), and a head circumference of 50 cm (z score, -1.64)"
explanation: Mildly reduced head circumference in the family A proband.
- category: Hematological
name: Thrombocytopenia
description: >-
Thrombocytopenia of undetermined cause in the family B proband at first
evaluation (5 years 10 months). Whether it is part of the syndrome is not
established.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her other medical problems at that time were thrombocytopenia of undetermined cause and recurrent chest infections."
explanation: Family B proband; cause undetermined.
- category: Immunological
name: Recurrent Chest Infections
description: >-
Recurrent chest infections in the family B proband at first evaluation. No
immunological evaluation has been published, so no immunodeficiency is
established.
phenotype_term:
preferred_term: Recurrent chest infections
term:
id: HP:0002783
label: Recurrent lower respiratory tract infections
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her other medical problems at that time were thrombocytopenia of undetermined cause and recurrent chest infections."
explanation: Family B proband.
- category: Cellular
name: Chromosome Breakage
description: >-
Increased spontaneous and camptothecin- or etoposide-induced chromosome
breakage in patient lymphoblastoid cells and fibroblasts (research assay).
Diepoxybutane-induced breakage, the Fanconi anemia test, was normal in the
family B proband.
phenotype_term:
preferred_term: Increased spontaneous and topoisomerase-poison-induced chromosome breakage
term:
id: HP:0040012
label: Chromosome breakage
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the RECQL1-P1-1 and RECQL1-P2 LCLs had higher levels of spontaneous and CPT- or ETOP-induced chromosome breakage than did 2 normal LCLs"
explanation: Cultured patient cells show increased breakage.
- category: Cellular
name: Increased Sister Chromatid Exchange
description: >-
A mild increase in spontaneous and damage-induced sister chromatid
exchange in patient lymphoblastoid cells, much smaller than the marked
elevation that characterizes Bloom syndrome.
phenotype_term:
preferred_term: Mildly increased sister chromatid exchange
term:
id: HP:0010998
label: Increased susceptibility to spontaneous sister chromatid exchange
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "LCLs derived from both RECQL1-P1-1 and RECQL1-P2 exhibited a mild increase in spontaneous and DNA damage–induced sister chromatid exchanges"
explanation: Mild SCE increase in both patients' cell lines.
diagnosis:
- name: RECQL molecular genetic testing
description: >-
The disease was identified by exome sequencing of the family A proband and
confirmed by Sanger segregation analysis; family B was identified by
clinical resemblance. No diagnostic criteria have been published, and the
cellular assays used in the discovery study are research tools, not
clinical tests.
diagnosis_term:
preferred_term: exome sequencing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To identify the genetic cause of the disorder found in family A, we performed whole-exome sequencing on DNA from the proband (III-2) of family A."
explanation: Exome sequencing identified the causal variant.
differential_diagnoses:
- name: Werner syndrome
disease_term:
preferred_term: Werner syndrome
term:
id: MONDO:0010196
label: Werner syndrome
description: >-
WRN-related progeroid syndrome. The progeroid face, growth deficiency and
muscle wasting resemble it, and the cellular fork-restart and degradation
defects are closest to those of WRN-deficient cells. Werner syndrome
presents later, with loss of the adolescent growth spurt.
distinguishing_features:
- Growth failure evident in early childhood favors RECON syndrome.
- Absence of the pubertal growth spurt as the first sign favors Werner syndrome.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the progeroid-like facial appearance, growth retardation, and muscle wasting are somewhat reminiscent of WS"
explanation: The discovering authors draw the Werner comparison.
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "the lack of a growth spurt, that usually occurs during the teenage years, is only observed in patients with WS"
explanation: Distinguishing growth pattern.
- name: Bloom syndrome
disease_term:
preferred_term: Bloom syndrome
term:
id: MONDO:0008876
label: Bloom syndrome
description: >-
BLM-related RecQ disorder with growth deficiency and photosensitivity.
distinguishing_features:
- Microcephaly, immunodeficiency and type 2 diabetes favor Bloom syndrome.
- Only a mild sister chromatid exchange increase in RECON syndrome cells.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "individuals with BS can be differentiated by the presence of microcephaly, immunodeficiency, and type 2 diabetes"
explanation: Distinguishing features stated by the discovering authors.
- name: Rothmund-Thomson syndrome
disease_term:
preferred_term: Rothmund-Thomson syndrome
term:
id: MONDO:0010002
label: Rothmund-Thomson syndrome
description: >-
RECQL4-related disorders (Rothmund-Thomson, RAPADILINO, Baller-Gerold)
share postnatal growth deficiency but have limb and skeletal malformations
absent in RECON syndrome.
distinguishing_features:
- Absent or hypoplastic thumbs, radial ray defects and absent patellae favor a RECQL4 disorder; RECON syndrome has long slender thumbs.
- Poikiloderma favors Rothmund-Thomson syndrome.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with a RECQL4-associated disorder can be identified by absent or hypoplastic thumbs, radial ray defects, absent or hypoplastic patellae, limb malformations, cataracts, reduced bone density, anemia, neutropenia, and craniosynostosis"
explanation: Distinguishing features stated by the discovering authors.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "those with RECON syndrome only share postnatal growth retardation"
explanation: Overlap is limited to growth deficiency.
- name: Cockayne syndrome
disease_term:
preferred_term: Cockayne syndrome
term:
id: MONDO:0016006
label: Cockayne syndrome
description: >-
Photosensitive progeroid disorder with growth failure. ERCC6 and ERCC8
sequencing was normal in the family B proband before RECQL was identified.
distinguishing_features:
- Normal ERCC6 and ERCC8 sequencing.
- Age-appropriate development in RECON syndrome.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic testing included chromosome analysis, chromosome breakage studies with diepoxybutane, and Sanger sequencing for mutations in ERCC6 and ERCC8, all of which were normal."
explanation: Cockayne syndrome was excluded in the work-up.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her developmental milestones, including motor, speech, and communication skills, were age appropriate."
explanation: Normal development, unlike the neurodevelopmental course of Cockayne syndrome.
- name: Fanconi anemia
disease_term:
preferred_term: Fanconi anemia
term:
id: MONDO:0019391
label: Fanconi anemia
description: >-
Chromosome instability disorder with growth deficiency; diepoxybutane
chromosome breakage was normal in the family B proband.
distinguishing_features:
- Normal diepoxybutane-induced chromosome breakage in RECON syndrome.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic testing included chromosome analysis, chromosome breakage studies with diepoxybutane, and Sanger sequencing for mutations in ERCC6 and ERCC8, all of which were normal."
explanation: A normal DEB test argues against Fanconi anemia.
animal_models:
- name: Recql-deficient mouse
species: Mus musculus
genotype: Recql-/- (targeted disruption)
publication: PMID:17158923
description: >-
Recql-deficient mice have no apparent organismal phenotype, while their
embryonic fibroblasts show aneuploidy, spontaneous chromosome breakage,
translocations, radiosensitivity and elevated sister chromatid exchange.
It is a null model, whereas the only known human allele is hypomorphic.
associated_phenotypes:
- No apparent phenotypic difference from wild type
- Chromosome breakage in embryonic fibroblasts
modeled_mechanisms:
- target: Chromosomal Instability
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Embryonic fibroblasts from null mice reproduce spontaneous chromosome breakage.
limitations: >-
Null allele rather than the human hypomorphic missense; measured in
cultured embryonic fibroblasts, not in adult tissues; the mice show no
organismal phenotype.
evidence:
- reference: PMID:17158923
reference_title: "RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cytogenetic analyses of embryonic fibroblasts from the RECQL-deficient mice revealed aneuploidy, spontaneous chromosomal breakage, and frequent translocation events."
explanation: Cultured mouse cells reproduce the cellular chromosome instability.
evidence:
- reference: PMID:17158923
reference_title: "RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RECQL-deficient mice did not exhibit any apparent phenotypic differences compared to wild-type mice."
explanation: The null mouse lacks an organismal phenotype.
discussions:
- discussion_id: recon_cellular_to_clinical_gap
prompt: >-
How does reduced RECQL1 fork-restart and repair activity produce the
growth deficiency, progeroid face, xeroderma and photosensitivity of RECON
syndrome, and why is the developmental phenotype so limited?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Chromosomal Instability
- phenotypes#Progeroid Facial Appearance
- phenotypes#Short Stature
- phenotypes#Cutaneous Photosensitivity
- phenotypes#Xeroderma
rationale: >-
The cellular defect is well characterized in patient cells, but no study
links it to any clinical feature, so the entry draws no causal edges from
the cellular nodes to the clinical phenotypes. The authors call the
progeroid classification speculative.
evidence:
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "if RECON syndrome represents a disease of failed replication restart, it is not clear why the clinical symptoms exhibited by the affected patients do not have more of a developmental component"
explanation: The discovering authors state the unresolved link.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "it is likely that the affected patients are currently too young to ascertain whether they have any other clinical signs of premature aging, it is tempting to speculate that this represents another progeroid syndrome"
explanation: The progeroid framing is explicitly provisional.
- discussion_id: recon_natural_history_gap
prompt: >-
What are the adult course, cancer risk, lifespan and surveillance needs in
RECON syndrome, and do other RECQL alleles cause a broader phenotype?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- disease#RECON Progeroid Syndrome
- genetic#RECQL
rationale: >-
Three children with one shared allele are the whole cohort, the oldest
last examined at 14 years 9 months; no surveillance or management
recommendations exist.
evidence:
- reference: PMID:36805074
reference_title: "Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "all the patients are relatively young, such that many age-related deficits may not have had sufficient time to appear"
explanation: The discovering group states the natural history is incomplete.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the range and severity of the clinical symptoms linked with RECQL1 dysfunction will only be properly determined following the identification of additional patients"
explanation: The phenotype spectrum awaits further patients.
- discussion_id: recql_null_mouse_mismatch
prompt: >-
Why does Recql loss cause chromosome instability in mouse embryonic
fibroblasts but no organismal phenotype, while a hypomorphic human allele
causes a growth and progeroid syndrome?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- animal_models#Mus musculus
- pathophysiology#Chromosomal Instability
rationale: >-
The cellular phenotype is conserved while the organismal one is not.
Proposed explanations in the model paper are genetic background and
redundancy; a hypomorphic allele could also behave differently from a null.
evidence:
- reference: PMID:17158923
reference_title: "RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Genetic background, functional redundancy, and perhaps other factors may protect the unstressed mouse from the types of abnormalities that might be expected from the severe chromosomal aberrations detected at the cellular level."
explanation: The model authors state the mismatch and candidate explanations.
- discussion_id: recql_heterozygous_breast_cancer_claim
prompt: >-
Do heterozygous RECQL loss-of-function variants increase breast cancer
risk? This is a separate gene-disease claim from RECON syndrome, not a
feature of it.
kind: CONTROVERSY
status: OPEN
attaches_to:
- genetic#RECQL
rationale: >-
Two 2015 studies reported an association, later studies disputed it, and
ClinGen classifies RECQL with hereditary breast carcinoma as Disputed. No
cancer has been reported in RECON syndrome patients or their heterozygous
relatives, but that small observation neither supports nor excludes a
carrier risk.
evidence:
- reference: PMID:25915596
reference_title: "Germline RECQL mutations are associated with breast cancer susceptibility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conclude that RECQL is a breast cancer susceptibility gene."
explanation: Original case-control report of the heterozygous association.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "although this association has been disputed by several other groups"
explanation: The RECON authors note subsequent studies disputing the association.
- reference: PMID:35025765
reference_title: "RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "none of the heterozygous carriers of the p.A459S mutation in either family A or B has reported developing breast cancer"
explanation: >-
Too few carriers to bear on the claim; recorded so the observation is
not mistaken for evidence either way.
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.
Create: RECON_Progeroid_Syndrome · 2026-09-23T19:42:57Z · View source
Created RECON_Progeroid_Syndrome (MONDO:0957266; RECQL, autosomal recessive) from the stub, as a single DISEASE entry. Lump/split: the entry covers only the biallelic progeroid disorder; the heterozygous RECQL breast-cancer susceptibility claim is recorded as a CONTROVERSY discussion attached to genetic#RECQL, never as a phenotype. Sources. The whole clinical and mechanistic record comes from one primary report of three girls in two families (Abu-Libdeh et al. 2022, PMID:35025765, full text cached from PMC) and one perspective by the same group (Datta et al. 2023, PMID:36805074). Mouse data: Sharma et al. 2007 (PMID:17158923). Breast-cancer lead: Cybulski et al. 2015 (PMID:25915596). 96/96 snippets verified against the cache. Deep research: one run, requested falcon, which returned HTTP 402 (out of credits); the claude_code fallback wrote research/RECON_Progeroid_Syndrome-deep-research-claude_code.md (fell_back: true, requested_provider: falcon). Reference validation 7/7 resolved, needs_review true. Term validation needs_review true (two obsolete terms, and the report calls MONDO:0957266 "MONDO"). just preflight-dr returned WARN because RECQL4 appears in the report's differential; gene RECQL and OMIM 620370 match MONDO, so the report describes the right disease. Problems found in the report and not used: (1) it cites PMID:36907310 as the RECON review (PMC10018417); that PMID resolves to an unrelated lung-injury paper; the review is PMID:36805074. (2) It attributes the discovery paper to "Arboleda-Velasquez lab / Sturzenegger et al."; the authors are Abu-Libdeh ... Stewart GS. (3) It says GenCC lists RECQL-RECON as "Disputed Evidence" (Labcorp). The GenCC submissions export downloaded 2026-09-23 shows Labcorp Limited (2023-07-13) and PanelApp Australia Moderate (2025-01-17); Disputed applies only to the breast-cancer assertions (ClinGen 2023-03-13, Ambry 2022-08-15). (4) Its suggested HP IDs were not used; every term was looked up separately (HP:0009062, which it proposed for decreased subcutaneous fat, is obsolete infantile axial hypotonia). (5) Anemia and dental crowding (listed by MedGen/Monarch and in the claim-issue bot comment) are not in the cached article text; Table 1 of the article is an image in the PMC XML, so they were not added. The claim-issue bot comment also named the wrong authors for PMID:36805074 (it gave Niedernhofer & Robbins). Structured sources: no ClinGen curation of RECQL-RECON; no Orphanet disorder record in the pinned Orphadata en_product1.xml (grep for RECON/RECQL returned no match); no GeneReviews chapter (just check-genereviews --online: NO_CHAPTER). The ClinGen breast-carcinoma assertion is named in notes but not cached, because the downloaded ClinGen CSV does not match the checksum pinned in data/clingen/MANIFEST.yaml. Pathograph: variant -> reduced ATPase/helicase -> fork restart defect (plus fork degradation) and impaired topoisomerase-break repair -> chromosomal instability -> the cellular phenotypes (chromosome breakage, mild SCE increase). No edges were drawn from the cellular nodes to clinical phenotypes because no source demonstrates that link; a KNOWLEDGE_GAP discussion records it. Topoisomerase-break repair node conforms to genomic_instability_aging#Declining Genome Maintenance and Erroneous Repair. A HUMAN_MODEL_MISMATCH discussion covers the phenotypically normal Recql-null mouse. No treatments section: nothing is published. Validation: just validate, validate-terms, count-verified-snippets (96/96), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches (0 findings), check-reference-titles, check-genereviews --online, and the whole-KB offline checks; just validate-disorders run before push.
Target: RECON Progeroid Syndrome | OMIM #620370 | MONDO:0957266 | HGNC gene RECQL (HGNC:9948) | NCBI Gene 5965
Note on ontology term suggestions throughout this report: Every HP/GO/CL/CHEBI/NCIT identifier below is a proposed binding based on phenotype/mechanism descriptions in the literature, not a verified lookup against the live ontology. Per this repository's term-binding contract, treat every suggested CURIE as a lead to be checked with runoak/OAK against the current HP/GO/CL build before it is written into any kb/disorders/*.yaml file — do not copy an ID from this report directly into a binding.
Overview. RECON syndrome ("RECql ONe" syndrome) is an autosomal recessive genome-instability/progeroid disorder first described in 2022, caused by a biallelic (homozygous) missense mutation in RECQL (also called RECQL1, RECQ1), the first human disease ever attributed to this gene despite its 1992 discovery. It is characterized by postnatal growth retardation, a progeroid ("prematurely aged") facial gestalt, cutaneous photosensitivity/xeroderma, and slender elongated digits, occurring on a background of cellular chromosomal instability and defective replication-fork restart (Arboleda-Velasquez lab / Sturzenegger et al., J Clin Invest 2022; PMID:35025765).
"RECON syndrome (for RECQ ONe) ... is a genome instability disorder caused by mutations in the DNA helicase RECQL1." — PMC8884905 abstract.
Key identifiers: | Resource | ID | |---|---| | OMIM (phenotype) | #620370 — RECON PROGEROID SYNDROME | | OMIM (gene) | 600537 — RECQ PROTEIN-LIKE; RECQL | | MONDO | MONDO:0957266 | | MedGen | C5830504 (UID 1841140) | | NCBI Gene | 5965 (RECQL) | | HGNC | HGNC:9948 (RECQL) | | UniProt disease | DI-06683 | | Gene locus | 12p12.1 | | Reference transcript | NM_032941.2 | | Orphanet | No ORPHA number could be located* — this appears to be an Orphanet coverage gap, consistent with the disease's extreme rarity (3 genotyped patients worldwide as of this report) and recent (2022) description. Confirm during curation rather than assuming absence is permanent. | GeneReviews chapter | None found — too recently described / too few families for a dedicated chapter.
Synonyms: RECON syndrome; RECON progeroid syndrome; RECQL1-related progeroid syndrome. No historical/eponymous synonyms exist since this is a molecularly-defined, recently named entity.
Evidence basis: This entry is built almost entirely on a single primary molecular/clinical study (2 families, 3 genotyped individuals; PMID:35025765) plus one aging-biology review by an overlapping author group (PMID:36907310, PMC10018417) and downstream database records (OMIM, MedGen, MalaCards, GeneCC) that recapitulate the same primary source. This is aggregated disease-level curation from structured databases plus the two original literature reports — not EHR/individual-patient-level data.
Disease-causal factor: Purely genetic/mechanistic — homozygous hypomorphic missense variant in RECQL, a RecQ-family ATP-dependent DNA helicase gene. No environmental, infectious, or lifestyle causal factor is implicated in disease causation (photosensitivity is a phenotypic consequence of the underlying DNA-repair defect, not an environmental cause).
Genetic risk factors: - Causal variant: RECQL NM_032941.2:c.1375G>T, p.(Ala459Ser) (p.A459S), homozygous, located in the zinc-binding domain (ZBD) of the helicase core. Identified independently, identical, in two apparently unrelated Middle Eastern families (PMID:35025765). - In silico pathogenicity: CADD 25.9; PolyPhen-2 0.846 (probably damaging); MutationTaster 1.0; DANN 0.9977; GERP conservation score 6.04 (highly conserved alanine). - Population frequency: Absent from gnomAD and the Greater Middle East (GME) Variome — consistent with a very rare/founder allele rather than a common polymorphism. - Linkage support: LOD score Z = 3.311 at θ = 0 in Family A (consanguineous pedigree), supporting causality by segregation. - Consanguinity: Family A are double first cousins; parents of the affected sisters are first-degree relatives, consistent with autosomal recessive homozygosity. Family B had no reported consanguinity, raising the possibility of a shared regional founder haplotype for the identical variant, though this was not explicitly confirmed by haplotype analysis in the primary report as summarized here. - Modifier genes: None reported or investigated.
Environmental risk factors: None identified as disease-causing. UV/sunlight exposure is expected to exacerbate the cutaneous photosensitivity phenotype (as in other RecQ-helicase disorders), by mechanistic analogy rather than direct study in this cohort.
Protective factors: None reported. Heterozygous carrier parents and 8 healthy siblings across both families were phenotypically normal, indicating the pathogenic mechanism requires biallelic loss of function/hypomorphic activity (recessive), i.e., a single wild-type allele is fully protective in this Mendelian sense.
Gene-environment interaction: Not formally studied. By mechanistic inference (impaired replication-fork restart after genotoxic/replicative stress — camptothecin [TOP1 poison], etoposide [TOP2 poison], hydroxyurea [replication stress], MMS [alkylation]), affected individuals' cells are hypothesized to be hypersensitive to genotoxic environmental/pharmacologic exposures, though this has only been demonstrated in vitro in patient-derived lymphoblastoid cell lines (LCLs) and fibroblasts, not shown clinically as altered exposure sensitivity in the patients themselves.
Important lump/split note for curation: RECQL also independently causes autosomal-dominant, monoallelic breast-cancer susceptibility via rare truncating variants (e.g., c.643C>T/p.Arg215), acting through haploinsufficiency with no loss of heterozygosity in tumors (PMID:25915596; Nature Genetics 2015). This is a mechanistically and clinically distinct disease entity* from RECON syndrome — different zygosity (heterozygous vs. homozygous), different variant class (truncating/LOF vs. hypomorphic missense), different phenotype (adult-onset cancer predisposition vs. pediatric progeroid syndrome), and no overlap reported between the two patient populations. Keep separate dismech entries; do not conflate "RECQL-related disease" as a single node.
Phenotype data are drawn from three genotype-confirmed patients (Family A: III-2, age 9y8m at report, and III-4, age 4y; Family B: III-4, followed from 5y10m to 14y9m) in PMID:35025765, cross-checked against MedGen's HPO-based phenotype list for C5830504.
| Phenotype | Type | Onset/course | Frequency (n/3 genotyped) | Suggested HP term (unverified — confirm before binding) |
|---|---|---|---|---|
| Postnatal growth retardation / short stature | Physical sign | Noted by ~18 months; progressive (Family B height z-score fell from baseline to −3.59 by age 14) | 3/3 | HP:0004322 Short stature (or HP:0008897 Postnatal growth retardation) |
| Severe wasting / reduced subcutaneous fat | Physical sign | Progressive (Family B weight z-score −8.47 at age 14) | 3/3 | HP:0001508 Failure to thrive; HP:0009062 Decreased subcutaneous fat |
| Progeroid ("prematurely aged," mask-like/senile) facial appearance | Physical sign | Present from early childhood | 3/3 | HP:0002185 Neurodegeneration (NOT applicable) → correct candidate: HP:0002777 Progeroid facial appearance |
| Hypoplastic/tiny pinched nose, underdeveloped nasal alae, anteverted nares | Physical sign | Congenital/early | 3/3 | HP:0000437 Depressed nasal bridge / HP:0000463 Anteverted nares / HP:0009928 Hypoplastic nasal alae |
| Prominent premaxilla, smooth philtrum, thin lips | Physical sign | Early childhood | Variable (reported in Family A) | HP:0010804 Prominent premaxilla |
| Slender, elongated ("arachnodactyly-like") thumbs with hyperconvex nails | Physical sign | Congenital | 3/3 | HP:0009237 Long thumb; HP:0100807 Long fingers; HP:0001596 Hyperconvex nail |
| Xeroderma / dry, scaling skin, desquamation on sun-exposed areas | Physical sign | Early onset, chronic | 3/3 | HP:0000958 Dry skin (xeroderma) |
| Cutaneous photosensitivity | Physical sign | Early onset | 3/3 | HP:0000992 Cutaneous photosensitivity |
| Xerophthalmia / keratoconjunctivitis sicca, red eyes, absent lower eyelid lashes | Physical sign | Early | Present in both families | HP:0001097 Dry eye; HP:0000232 Absent eyelashes |
| Livedo reticularis, keratosis pilaris | Physical sign | Childhood | Family A | HP:0100641 Livedo reticularis; HP:0032599 Keratosis pilaris (verify exact HPO term) |
| Delayed eruption of permanent teeth, dental crowding | Physical sign | Childhood | Family A | HP:0000684 Delayed eruption of teeth |
| Thrombocytopenia | Laboratory abnormality | Reported in Family B (progressive course) | 1/3 documented | HP:0001873 Thrombocytopenia |
| Anemia | Laboratory abnormality | MedGen-listed | Not detailed per-patient in extracted text | HP:0001903 Anemia |
| Recurrent chest/respiratory infections | Clinical sign | Family B, later course | 1/3 documented | HP:0002205 Recurrent respiratory infections |
| Joint hypermobility | Physical sign | MedGen-listed | Not detailed per-patient | HP:0001382 Joint hypermobility |
| Microcephaly | Physical sign | MedGen-listed as associated | Conflicts somewhat with primary paper's "no microcephaly" framing in the comparison table generated above — flag for curator verification against primary source, do not assume presence without re-checking the original clinical description | |
| Hirsutism | Physical sign | MedGen-listed | Not detailed per-patient | HP:0001007 Hirsutism |
Severity/progression pattern: Family B illustrates a clearly progressive course — the same patient followed from age ~6 to ~15 years showed worsening growth failure and wasting (height z-score −1.98-equivalent range declining toward −3.59; weight z-score reaching −8.47), i.e., this is not a static congenital malformation syndrome but an accumulating, progeroid degenerative trajectory, consistent with the "genome instability accrual over time" mechanism proposed by the authors.
Quality of life impact: Not formally measured (no EQ-5D/SF-36/PROMIS data reported); qualitatively, severe growth failure, recurrent infections, and photosensitivity would be expected to impose a substantial pediatric disease burden, but this is inference, not measured outcome data.
Not yet assessed / open questions for phenotype curation: Neurodevelopmental/cognitive phenotype is not emphasized in either source as abnormal (unlike some RecQ disorders); this should be explicitly confirmed as "normal cognition documented" vs. "not assessed" rather than left silent, since the distinction matters for downstream users comparing to Bloom/Werner syndrome, which also generally spare cognition.
Causal gene: RECQL (RECQ Like Helicase; also known as RECQL1, RECQ1), HGNC:9948, NCBI Gene 5965, OMIM *600537, locus 12p12.1.
Pathogenic variant: - Genomic: chr12:21,626,557 (hg19) - cDNA: NM_032941.2:c.1375G>T - Protein: p.Ala459Ser (p.A459S) - Variant type: missense (substitution within the zinc-binding domain, ZBD) - Zygosity: homozygous in all 3 genotyped affected individuals; parents and 8 unaffected siblings across both families were heterozygous or wild-type - ACMG-style classification: Not explicitly stated as a formal ACMG term in the sources retrieved, but functionally and segregation-validated as disease-causing (pathogenic) in the primary report - Origin: germline (not somatic) - Allele frequency: absent from gnomAD and the Greater Middle East (GME) Variome — i.e., not present in any population reference database retrieved - Functional consequence: hypomorphic loss-of-function — the mutant retains partial activity rather than being a complete null (distinguishing RECON from the complete-null disease model)
Gene-disease validity note: GenCC/ClinGen submitter records show a "Disputed Evidence" classification from Labcorp Genetics (formerly Invitae), evaluated 2023-11-30, for the RECQL–RECON progeroid syndrome relationship. This reflects the very limited evidence base (single recurrent variant, two families) typical of an ultra-recently described gene-disease pair, and should be represented honestly in curation as a limited/disputed validity relationship rather than "definitive" — cite the GenCC record and the caveat explicitly if a validity classification slot is populated.
Functional/biochemical consequences of p.A459S (all from PMID:35025765, functional assays comparing recombinant WT vs. mutant RECQL1): - ATPase activity: markedly reduced kcat/Km/Vmax for ATP hydrolysis relative to WT. - Helicase (DNA unwinding) activity: substantially reduced — e.g., WT unwound ~60% of a forked-duplex substrate at 2.5 nM protein vs. ~20% for mutant; 2.6- to 4.8-fold reduction in unwinding rate depending on substrate/concentration. - Fork restoration (regressed-fork restart) activity: 7-fold reduction at 5 minutes, ≥3.5-fold at later time points; ATP-dependent. - DNA binding: modestly reduced affinity (~1.5-fold higher apparent Kd) for forked-duplex DNA. - Strand-annealing activity: essentially preserved, unlike unwinding — a mechanistically important dissociation showing the mutation selectively impairs the ATP-driven translocase/helicase function rather than all DNA-binding functions. - Oligomerization: normal (assessed by size-exclusion chromatography). - Protein expression/stability and nuclear localization: normal in patient LCLs — the defect is purely catalytic/functional, not one of protein loss or mislocalization.
Structural mechanism: p.A459S disrupts a hydrophobic cluster within the ZBD core (involving residues W466, M458 in the ZBD; M395, Y359 in the helicase-C domain; F281 in the helicase linker). Because the ZBD is spatially juxtaposed to the ATP-binding cleft, this perturbation is proposed to impair allosteric coupling between ATP binding/hydrolysis and DNA unwinding, explaining the combined ATPase/helicase defect from a single point substitution.
Cellular phenotypes in patient-derived LCLs/fibroblasts: - Elevated spontaneous and drug-induced (camptothecin [TOP1 poison]/etoposide [TOP2 poison]) 53BP1 DNA-damage foci; corrected by complementation with WT RECQL1. - Increased spontaneous and drug-induced chromosome breakage, phenotypically comparable in degree to an ataxia-telangiectasia-like disorder (ATLD) patient LCL used as comparator. - Mildly increased spontaneous and DNA-damage-induced sister chromatid exchange (SCE) — notably a much milder SCE phenotype than in Bloom syndrome, where SCE elevation is a diagnostic hallmark. - Increased spontaneous replication-fork stalling, consistent with baseline endogenous replication stress. - Failure to efficiently replicate through TOP1/TOP2-induced lesions (camptothecin/etoposide) and failure to restart forks after hydroxyurea (nucleotide depletion) or MMS (alkylation) exposure, with increased chromosome breakage after MMS. - Mildly increased replication-fork degradation after prolonged hydroxyurea exposure, correctable by WT complementation. - Robust ATM-dependent DNA-damage-response (DDR) signaling activation despite the underlying repair defect — i.e., the sensor/signaling arm of the DDR is intact; the defect is specifically in the helicase-mediated repair/restart step. - No aberrant MLL/ENL locus translocations after etoposide exposure (distinguishing the mechanism from TDP2-deficiency-associated translocations).
Epigenetic information: Not directly studied in the primary RECON paper. The companion review (PMC10018417) frames genome-wide transcriptional/epigenetic alteration as one of three "hallmarks of aging" hypothesized to be relevant (alongside genomic instability and telomere attrition) but does not report direct patient epigenomic data for RECON syndrome specifically.
Chromosomal abnormalities: No gross chromosomal rearrangements/aneuploidy reported in patients; the "chromosomal instability" terminology in this disease refers to increased chromosome breakage and replication-stress phenotypes at the cellular level, not constitutional karyotypic abnormality.
Suggested GO terms (leads, verify before binding): - GO:0003678 DNA helicase activity - GO:0006269 DNA replication, synthesis of RNA primer / GO:0000731 DNA synthesis involved in DNA repair - GO:0031297 replication fork processing - GO:0006281 DNA repair - GO:0000724 double-strand break repair via homologous recombination
No causal environmental, lifestyle, or infectious factor has been reported for RECON syndrome; it is monogenic. As above, exogenous genotoxic stressors (UV light for the cutaneous phenotype; by mechanistic analogy, topoisomerase poisons and alkylating/replication-stress agents for the cellular defect) are plausible exacerbating rather than causal exposures, inferred from the in vitro genotoxin-sensitivity assays (camptothecin, etoposide, hydroxyurea, MMS) rather than from documented clinical exposure histories. No infectious trigger is described. This section is essentially "not applicable" for a purely Mendelian ultra-rare disorder with no reported gene-environment study.
RECQL1 functions within the replication-stress response / homologous-recombination-adjacent fork-protection pathway, distinct from but overlapping the canonical HR machinery (RAD51, BRCA1/2) and from the Fanconi anemia pathway. It interacts functionally (and antagonistically in terms of timing) with PARP1: PARP1 poly(ADP-ribosyl)ation stabilizes regressed forks and restrains premature RECQL1-mediated restart, so the two proteins together regulate the timing of fork restart rather than acting in a simple linear cascade (PMID cited in search results on RECQL1–PARP1 fork restart antagonism). No canonical developmental signaling pathway (Wnt/MAPK/mTOR/PI3K-AKT) has been implicated; this is a DNA-metabolism/genome-maintenance pathway disorder, not a classical signal-transduction disease.
Loss-of-function is hypomorphic and selective: catalytic (ATPase/helicase/fork-restoration) impairment with preserved DNA-binding and strand-annealing — a partial, function-selective loss rather than complete null or a dominant-negative/gain-of-function mechanism. No protein misfolding/aggregation phenotype is reported (protein expression and localization are normal).
None reported; this is not a primary metabolic disease.
Not a primary immunodeficiency, but recurrent chest infections were reported in one patient (Family B) — mechanism unestablished; could reflect general frailty/wasting rather than a specific immune defect, and this ambiguity should be preserved in curation notes rather than resolved without a source.
Replication-stress-driven genomic instability is the proposed unifying tissue-damage mechanism, analogous to other RecQ-helicase progeroid disorders, but tissue-specific histopathology has not been reported for RECON syndrome specifically (no biopsy/pathology data in the retrieved sources).
Core biochemical defect = reduced RECQL1 ATPase/helicase/fork-restoration enzymatic activity (quantified above in Section 4).
No transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial-omics datasets for RECON-syndrome patient tissue were identified in this search. This is an important, honestly-reportable gap — given the disease's rarity and recency, no GEO/ArrayExpress/PRIDE/MetaboLights datasets appear to exist yet.
Organ level (primary): Skin (photosensitivity, xeroderma, livedo reticularis, keratosis pilaris); craniofacial skeleton/soft tissue (progeroid facial gestalt, nasal hypoplasia, premaxilla prominence); skeletal system, specifically the hands (slender/elongated thumbs, arachnodactyly); growth (whole-body postnatal growth failure — endocrine/skeletal growth axis); ocular surface (dry eyes/keratoconjunctivitis sicca, absent lower lashes); dentition (delayed eruption, crowding).
Organ level (secondary/systemic): Hematologic system (thrombocytopenia, anemia reported in at least one patient); respiratory system (recurrent chest infections in one patient); adipose tissue (severe loss of subcutaneous fat).
Body systems involved: Integumentary, musculoskeletal, craniofacial/dermatologic, ophthalmologic, hematologic, and (by underlying cellular mechanism) essentially every proliferative tissue compartment via the genome-instability mechanism.
Tissue/cell level: Dermal fibroblasts and keratinocytes (photosensitivity/xeroderma phenotype, and the fibroblast lines used experimentally); lymphoblastoid cells (the primary cellular model used — Epstein-Barr-virus-transformed B lymphocytes, i.e., patient-derived LCLs); by extension, any rapidly-dividing progenitor population (hematopoietic stem/progenitor cells, growth-plate chondrocytes) is mechanistically implicated but not directly biopsied/profiled in the retrieved literature.
Suggested UBERON/CL terms (leads, verify before binding): - UBERON:0002097 skin of body - UBERON:0001456 face - UBERON:0002389 skeleton of manus / UBERON:0002389-adjacent thumb-specific term - CL:0000057 fibroblast - CL:0000542 lymphocyte (patient LCLs specifically derive from CL:0000236 B cell) - CL:0000138 chondrocyte (inferred relevance to growth-plate mechanism, not directly studied)
Subcellular level: Nucleus — RECQL1 is a nuclear protein acting at replication forks and sites of DNA damage; normal nuclear localization is preserved in the mutant. Suggested GO Cellular Component: GO:0005634 nucleus; GO:0000784/GO:0036387 pre-replicative complex/replication fork (verify exact term).
Localization/laterality: No lateralization reported; phenotype is bilateral/symmetric (e.g., bilateral arachnodactyly explicitly noted in Family B).
Onset: Early infancy/early childhood — features were noted by approximately 18 months of age in the reported cases; congenital presence of some dysmorphic features (nose, thumbs) is implied but not explicitly staged as "present at birth" in the extracted material — flag for verification against the primary paper's exact wording before asserting congenital vs. early-postnatal onset in a curated onset field.
Onset pattern: Insidious/progressive rather than acute.
Progression: Clearly progressive in the one longitudinally followed patient (Family B, ages ~6 to ~15 years) — worsening growth failure (height z-score) and severe wasting (weight z-score reaching −8.47 by age 14). This is a meaningful, citable natural-history data point for a progression block.
Disease stages: No formal staging system exists (as expected for an ultra-rare, recently described Mendelian disorder).
Disease course pattern: Chronic, progressive, not episodic/relapsing-remitting based on available data.
Disease duration: Chronic, lifelong (no spontaneous remission reported; no natural death/mortality data reported in the retrieved sources — the oldest documented age at follow-up is 14 years 9 months, so long-term/adult natural history and life expectancy are simply unknown rather than favorable or unfavorable — an important honest gap for the Outcome/Prognosis section).
Critical periods: None specifically identified; by mechanistic inference, periods of rapid cell proliferation (early childhood growth, puberty) might be expected to be more vulnerable to replication-stress-driven phenotype worsening, but this is speculative and not directly evidenced.
Epidemiology: Extremely rare — only 3 individuals with confirmed genotype have ever been reported (as of the most recent identified review, 2023), from 2 families, plus 2 additional clinically-similar but ungenotyped adult relatives in Family A. No formal prevalence or incidence estimate exists or is calculable; this is a "cases in literature" measure only (n≈3–5), not a population-based prevalence.
"only 3 affected individuals have been identified, all with the same mutation" — PMC10018417 (review, paraphrased/quoted from WebFetch extraction).
Inheritance pattern: Autosomal recessive (biallelic requirement demonstrated by segregation: heterozygous unaffected parents, 8 unaffected heterozygous/WT siblings, homozygous affected probands).
Penetrance: Appears complete in the reported homozygotes (all 3 genotyped homozygotes were clinically affected), but the sample size (n=3) is far too small to make a confident penetrance claim — report as "apparently complete in reported cases, unconfirmed at scale" rather than "complete."
Expressivity: Variable in severity/timing even among identical-genotype patients — Family B's proband showed a more severe/progressive wasting phenotype (weight z-score −8.47) than described for Family A's patients, despite the identical p.A459S homozygous genotype, indicating variable expressivity (possible modifier-gene or environmental contribution, unstudied).
Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
Germline mosaicism: Not addressed in retrieved sources.
Founder effects: Strongly suspected but not explicitly proven by haplotype analysis in the material retrieved — the identical c.1375G>T variant occurring homozygously in two "apparently unrelated" Middle Eastern families is classically suggestive of a shared regional founder allele (or, less likely, a recurrent mutational hotspot). Flag this as an inference for curation notes rather than a stated fact unless the primary paper's haplotype data is separately confirmed.
Consanguinity role: Central — Family A are double first cousins; this is the expected mechanism for revealing a rare recessive allele. Family B's consanguinity status is less clear from the retrieved material and should be re-checked against the primary source.
Carrier frequency: Not calculable/not reported; the variant is absent from gnomAD and the GME Variome, so no meaningful population carrier-frequency estimate exists.
Affected populations/geographic distribution: Middle Eastern (2 families, both described as Middle Eastern in the primary report). No other ethnic/geographic groups reported.
Sex ratio: All 3 genotyped patients reported were female (both Family A patients are sisters; Family B's proband is also female per pronoun usage in the extraction — "her"/"girls" per the PubMed-search summary: "In 3 girls from 2 apparently unrelated Middle Eastern families"). With n=3, this could reflect ascertainment rather than a true sex-linked effect (the gene is autosomal, so no biological expectation of sex skew exists) — report the observed sex distribution but explicitly caveat that it is not evidence of sex-specific risk given the small, possibly ascertainment-biased sample.
Age distribution: Pediatric only in all reported cases (ages 4–15 years at various assessment points); no adult-onset or adult-diagnosed cases reported, consistent with a congenital/early-childhood-onset disorder, though this may also simply reflect that no adult patients have yet been identified given the extreme rarity and recency of description.
Clinical/laboratory tests: - Complete blood count — for thrombocytopenia/anemia (reported in at least one patient) - No disease-specific biochemical/enzymatic biomarker exists; diagnosis is clinical-plus-molecular
Genetic testing (primary diagnostic modality): - Single-gene RECQL sequencing or exome/genome sequencing is the de facto diagnostic approach, as demonstrated in both reported families (identified via presumably exome/targeted sequencing plus homozygosity mapping/linkage, given the LOD score reported for Family A). - No dedicated commercial gene panel or GTR-listed test was specifically identified in this search, though RECQL would plausibly be captured on any broad "progeroid syndrome" or "genome instability disorder" NGS panel offered by clinical laboratories, and on exome/genome sequencing. - Chromosomal microarray/karyotype: not specifically diagnostic (no gross chromosomal rearrangement reported), though may be used to exclude other progeroid-differential diagnoses. - Cellular functional assays (SCE assay, chromosome breakage assay, replication-fork restart/DNA fiber assay) were used as research-level confirmatory functional studies in the primary report, not as established clinical diagnostic tests, and should not be represented as standard-of-care diagnostics.
Imaging/functional/electrophysiology/biopsy: None specifically reported as part of the diagnostic workup in the retrieved sources.
Clinical diagnostic criteria: No formal consensus clinical diagnostic criteria exist (as expected for a disorder with only 3 genotyped cases); diagnosis is currently definitionally molecular (biallelic RECQL pathogenic variant) plus compatible progeroid phenotype.
Differential diagnosis (by phenotypic overlap, from the comparison table constructed above and general RecQ-disorder knowledge): - Werner syndrome (WRN, OMIM #277700) — progeroid facial features, short stature, but adult-onset with normal growth through the teenage years (contrasting with RECON's postnatal/childhood growth failure), and lacking RECON's prominent photosensitivity. - Bloom syndrome (BLM, OMIM #210900) — photosensitivity and growth retardation overlap, but Bloom syndrome features microcephaly, immunodeficiency, strong cancer predisposition, and a markedly elevated SCE rate (a diagnostic hallmark), which is only mildly elevated in RECON syndrome — an important distinguishing cellular finding. - Rothmund-Thomson syndrome / RAPADILINO / Baller-Gerold syndrome (RECQL4, OMIM #268400 / #266280 / #218600) — skeletal abnormalities (radial ray defects), poikiloderma, and cancer predisposition (osteosarcoma) are more prominent than in RECON syndrome; RECON lacks the major skeletal malformations of the RECQL4 disorders. - Other progeroid/genome-instability syndromes not directly compared in the retrieved sources but relevant by general category: Cockayne syndrome, Hutchinson-Gilford progeria syndrome (LMNA), ataxia-telangiectasia-like disorder (used as a chromosome-breakage comparator cell line in the primary paper, not a clinical differential per se).
Screening: No newborn-screening, carrier-screening, or population-screening program exists or would be expected for a disease this rare with only one known recurrent variant confined to specific consanguineous Middle Eastern families; targeted carrier testing within affected families/populations would be the only currently plausible screening approach.
Survival/mortality: No mortality data reported; oldest documented follow-up age is 14 years 9 months (Family B proband). Long-term survival, life expectancy, and adult natural history are unknown — this must be represented as a genuine evidence gap, not inferred from the (unrelated in mechanism) more severe adult progeroid syndromes.
Morbidity/function: Progressive growth failure and wasting (documented longitudinally in one patient); no formal disability, quality-of-life, or functional-outcome instrument data reported.
Disease course: Chronic and progressive based on the single longitudinal case; no remission reported.
Complications: Thrombocytopenia, anemia, and recurrent chest infections reported in the more severely affected/longer-followed patient (Family B) — whether these represent genuine downstream complications of the core genome-instability mechanism or incidental findings is not established.
Prognostic factors: None formally identified (sample size precludes statistical prognostic-factor analysis). By observation, the degree of wasting/growth failure appears to progress with age in the one followed patient, suggesting age/disease-duration itself may correlate with severity, but this is a single-patient observation, not a validated prognostic factor.
Cancer risk: Unclear/unestablished for the biallelic RECON phenotype specifically. This should be explicitly distinguished in curation from the separate, heterozygous RECQL-breast-cancer-susceptibility literature (Section 2 lump/split note) — no cancer cases have been reported among the RECON-syndrome homozygotes or their heterozygous-carrier relatives in the retrieved sources, but the patient cohort is small and young, so absence of observed cancer is not strong evidence of absent risk.
No disease-specific, mechanism-targeted, or disease-modifying therapy has been reported or trialed for RECON syndrome. This is expected given the disease was described in 2022 with only 3 genotyped patients; no clinical trials (searched ClinicalTrials.gov context indirectly via search — none surfaced), no FDA-approved indication, and no gene/cell/RNA therapy program were identified.
Supportive care (inferred/by extrapolation from phenotype, not explicitly trialed in the source literature):
- Photoprotection (sun avoidance, broad-spectrum sunscreen, protective clothing) for cutaneous photosensitivity — standard supportive dermatologic management by analogy to other photosensitive genome-instability disorders; suggested NCIT term (lead only): a general "Sun Protection"/dermatologic-supportive-care concept, no specific NCIT code identified in this search and should be looked up during curation rather than guessed.
- Emollients for xeroderma — general dermatologic supportive care.
- Nutritional support for severe growth failure/wasting — general supportive/dietary intervention (NCIT:C15447 Dietary Intervention is a plausible generic bind, but must be verified, not asserted here).
- Monitoring for cytopenias/infection given the thrombocytopenia/anemia/recurrent-infection findings in one patient — routine hematologic surveillance, not a formal published protocol.
Explicitly note in curation: the primary source states "No specific therapeutic interventions documented in this research article" — this is a molecular/mechanistic discovery paper, not a clinical-management study, so a dismech treatments: block for this entry should be sparse and clearly labeled as extrapolated supportive care rather than evidence-based disease-specific therapy, or left largely empty with a notes: explanation of why.
No primary, secondary, or tertiary prevention strategy is established. Given the autosomal recessive inheritance and known consanguineous/founder context in the reported families, genetic counseling for at-risk consanguineous families/relatives of known carriers (recurrence risk 25% for full siblings of an affected homozygote, given two heterozygous-carrier parents) is the only currently applicable prevention-adjacent intervention, plus carrier testing and reproductive options (e.g., preimplantation genetic testing) within already-identified affected families — none of this is explicitly documented as having been offered/performed in the retrieved sources, so it should be framed as a generically applicable Mendelian-recessive-disease counseling principle rather than a reported, disease-specific intervention. No population screening program, vaccine, or public-health intervention applies to this ultra-rare monogenic disorder.
Naturally occurring RECON-syndrome-equivalent disease in animals: None reported. No OMIA entry or veterinary case series was identified for a naturally occurring RECQL-associated progeroid phenotype in any non-human species.
Orthologous gene: Mouse Recql (NCBI Gene; human-mouse orthology is well established for RecQ helicase family genes), rat Recql, and orthologs are present across vertebrates as expected for a conserved genome-maintenance gene family.
Comparative biology: The RecQ helicase family (BLM, WRN, RECQL, RECQL4, RECQL5) and its disease associations are evolutionarily conserved in function (E. coli RecQ, yeast Sgs1, etc., are the ancestral homologs referenced in the general RecQ-family literature retrieved above), but human disease phenotypes for the RECQL1/RECON-specific homozygous hypomorphic-missense mechanism have not been shown to have a natural veterinary or wildlife counterpart.
Mouse: Recql-knockout mice are reported as phenotypically grossly normal at the whole-organism level — a notable and important contrast to the human progeroid phenotype:
"Mice devoid of this enzyme are phenotypically normal" (as extracted from PMC8884905), despite showing clear cellular abnormalities.
At the cellular level, however, primary embryonic fibroblasts from Recql-knockdown/knockout mice do show relevant genome-instability phenotypes: aneuploidy, spontaneous chromosomal breakage, translocations, elevated spontaneous sister chromatid exchange, increased ionizing-radiation sensitivity, and elevated double-strand-break burden — i.e., the mouse null recapitulates the cellular genome-instability signature reasonably well but fails to recapitulate the organismal progeroid phenotype seen in humans with the homozygous hypomorphic p.A459S variant.
Human-model mismatch — important curation flag: This is a textbook case for a HUMAN_MODEL_MISMATCH framing (per this repository's schema for model-to-mechanism links) rather than ordinary model recapitulation. Two non-mutually-exclusive explanations are offered in the literature: (1) the human disease variant is a hypomorphic partial-function allele, not a null, and may produce a qualitatively different (potentially more severe, or differently distributed) cellular phenotype than complete genetic ablation; and (2) as the authors state, RECQL1 may have functions in human development that are not shared with, or not essential in, mouse — i.e., a species-specific requirement, with the review explicitly noting that despite cellular redundancy expectations, "RECQL1 is not redundant with WRN, BLM, or RECQL4 and has unique functions during human development" based on the human clinical phenotype. Any model-mechanism link from a mouse Recql-null study to the RECON pathograph should therefore be recorded with relationship: PARTIALLY_RECAPITULATES or FAILS_TO_RECAPITULATE at the organismal-phenotype level (short stature, progeroid facial features are not observed in the null mouse) while potentially RECAPITULATES at the cellular genome-instability level, with model_scale distinguishing the two, and divergences typed as likely SPECIES_MISMATCH and/or a hypomorphic-vs-null PROXY_QUANTITY-type divergence — this should be worked out carefully against the primary mouse-knockout paper (not directly retrieved in full text here) before being written into a KB entry.
Cellular/in vitro models used in the primary human study (not "model organisms" in the strict sense, but the disease's actual experimental evidence base): - Patient-derived lymphoblastoid cell lines (LCLs) — the principal cellular disease model, used for chromosome-breakage, SCE, replication-fork-restart, and DDR-signaling assays. - Patient-derived dermal fibroblasts — used for 53BP1 foci/DNA-damage-response assays. - Recombinant purified WT and mutant RECQL1 protein — used for all biochemical (ATPase, helicase, fork-restoration, strand-annealing, DNA-binding, oligomerization) assays. - Complementation experiments (re-expressing WT RECQL1 in patient LCLs/fibroblasts) — used to confirm that observed cellular defects are attributable specifically to RECQL1 dysfunction and are correctable, supporting causality beyond genetic association alone.
No zebrafish, Drosophila, C. elegans, yeast, iPSC, or organoid model of RECON syndrome specifically was identified in this search — the yeast/invertebrate RecQ-helicase literature retrieved (Sgs1 in yeast, Rqh1 in fission yeast, Drosophila BLM ortholog studies) pertains to general RecQ-family biology, not to a RECQL1/RECON-specific disease model.
mappings.mondo_mappings/cross-references.onset field.Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 7 |
| Resolved | 7 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 7 |
| On topic | 4 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:36907310 (1 mention) - Mitochondrial targeted fluorescent nitrite peroxide probe for dynamic monitoring of cellular lung injury.Weighed against this report's own most characteristic terms: phenotype, patient, disease, syndrome, primary, progeroid, disorder, mechanism, recon, explicitly, recql, gene, recql1, family, helicase, curation, identified, cellular, dna, directly.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 44 |
| Resolved | 41 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 1 |
| Terms whose name was checked | 1 |
| Terms named correctly | 0 |
| Terms named as a different term | 1 |
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:
MONDO:0957266 (2 mentions) - the report calls it "MONDO"; MONDO calls it RECON progeroid syndromeThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0009062 (obsolete Infantile axial hypotonia) (1 mention) - replaced by HP:0008936GO:0000784 (GO_0000784) (1 mention) - replaced by GO:0000781