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Classifications

Harrison's Part

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected children are homozygous or compound heterozygous for NSMCE3 missense variants and their parents are healthy heterozygous carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Homozygous and compound heterozygous mutations were found in 2 independent kindreds, in which 4 children died in early childhood after developing rapidly progressive pulmonary disease following viral pneumonia."

Biallelic variants in affected children of two unrelated kindreds.

PMID:33741030 SUPPORT Human Clinical

"The autosomal recessive lung disease immuno-deficiency and chromosome breakage syndrome (LICS), caused by missense mutations in NSMCE3, was first described in 2016 [1]."

Independent series restating the autosomal recessive mode of inheritance.

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Mechanistic Hypotheses

2

Viral pneumonia in combined immunodeficiency triggers the lung injury

immunodeficiency_triggered_lung_injury ALTERNATIVE

Evidence balance 1 support 1 refute

The founding report linked the lung disease to viral pneumonia in infants with a combined T and B cell defect. This motivated a trial of haematopoietic stem cell transplantation, which did not prevent fatal lung disease. Five later patients developed the same course without infection and with normal immune evaluations, so the immune defect is at most a contributing factor in some patients.

Pathograph links

Combined T and B Cell Dysfunction -> Progressive Diffuse Alveolar Damage and Interstitial Lung Injury INDIRECT UNKNOWN INTERMEDIATES The original model: viral pneumonia in an immunodeficient infant triggers progressive, irreversible lung damage. Contested by the occurrence of the same fatal lung course in patients with normal immune studies and no infection.

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"This disorder, designated LICS, which expands the spectrum of chromosomal breakage syndromes, is associated with progressive, severe PARDS following viral pneumonia, resulting in death in early childhood of the affected individuals described here."

The founding report's association of the lung disease with preceding viral pneumonia.

PMID:33741030 REFUTE Human Clinical

"In conclusion, we present five recently identified LICS patients who developed fatal lung disease without signs of infection and who expressed a variable immunological phenotype."

Fatal lung disease without infection argues against an obligatory infectious trigger.

SMC5/6 destabilization causes lung injury independently of the immune defect

intrinsic_systemic_lung_disease EMERGING

Evidence balance 2 support

The later series reframed LICS as a childhood interstitial lung disease of undefined etiology driven by the systemic SMC5/6 defect rather than by immunodeficiency. Candidate routes named in the literature, none tested in lung tissue, include a specific consequence of losing the NSMCE3-NSMCE4 interface, and loss of the SMC5/6 complex's role in silencing transcription from viral circular DNA genomes, which could permit exaggerated viral or inflammatory responses.

Pathograph links

SMC5/6 Complex Destabilization -> Progressive Diffuse Alveolar Damage and Interstitial Lung Injury INDIRECT UNKNOWN INTERMEDIATES Lung injury that develops without preceding infection and with normal immune studies suggests a route from SMC5/6 loss to alveolar damage that does not pass through the immune defect. The cell type and intermediate steps are unknown; the founding authors speculated that loss of the NSMCE3-NSMCE4 interface specifically underlies the pulmonary phenotype.

Show evidence (2 references)

PMID:33741030 SUPPORT Human Clinical

"Lung transplantation was also shown not to be beneficial in LICS ... likely because of the underlying systemic nature of this disorder."

Authors attribute treatment failure to a systemic, not purely immune, disease.

PMID:33741030 SUPPORT BACKGROUND Other

"Data on the function of the SMC5/6 complex suggests it plays a role in prevention of transcription from viral circular DNA genomes and that it thereby has a suppressive role in the development of viral infections and inflammatory processes"

Background statement of a candidate route; the cited work is on viral restriction in other systems, not on LICS lung tissue.

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Discussions and Knowledge Gaps

1

How does SMC5/6 destabilization cause diffuse alveolar damage in infancy, and what part, if any, does the variable combined immunodeficiency play?

KNOWLEDGE GAP OPEN lics_lung_injury_mechanism

Attached to

pathophysiology#Progressive Diffuse Alveolar Damage and Interstitial Lung Injury mechanistic_hypotheses#immunodeficiency_triggered_lung_injury mechanistic_hypotheses#intrinsic_systemic_lung_disease

The founding report linked the lung disease to viral pneumonia in immunodeficient infants, but five later patients died of the same lung disease with normal immune studies and no infection, and stem cell transplantation did not prevent it. None of the cited studies examined which lung cell type is affected, whether alveolar epithelial cells accumulate DNA damage, or whether loss of SMC5/6 restriction of viral episomes contributes.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Although it is known that NSMCE3 is part of the SMC5-SMC6 complex involved in DNA repair, the exact pathophysiology of LICS has not yet been elucidated."

Authors state the pathophysiology is unexplained.

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Pathophysiology

7

NSMCE3 Missense Protein Destabilization

The patient missense variants sit in the C-terminal winged-helix B domain (p.Pro209Leu) and its extension (p.Leu264Phe) of NSMCE3. Both abolish binding to NSMCE4, and p.Pro209Leu also strongly reduces binding to NSMCE1 and makes the recombinant protein prone to C-terminal truncation. Endogenous NSMCE3 falls below the detection limit in patient fibroblasts; because loss of other SMC5/6 subunits is embryonic lethal in mice, the authors infer that some NSMCE3 persists at low level.

fibroblast CL:0000057

NSMCE3 hgnc:7677

Genetic context NSMCE3 hgnc:7677 variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Biallelic missense variants, homozygous p.Leu264Phe or compound heterozygous p.Leu264Phe/p.Pro209Leu. Partial rather than complete loss of function is the authors' inference from the embryonic lethality of SMC6 and NSMCE2 loss in mice; residual NSMCE3 was not directly measured.

double-stranded DNA binding by the NSE1/NSE3/NSE4 module GO:0003690 ↓ DECREASED

Downstream

SMC5/6 Complex Destabilization Loss of the NSMCE3-NSMCE4 interface weakens the subcomplex that bridges the SMC5 and SMC6 subunits, so the complex as a whole is destabilized.

Show evidence (4 references)

PMID:27427983 SUPPORT In Vitro

"The Leu264Phe mutation of the affected individuals A-D abolished binding of NSMCE3 to NSMCE4, while its interaction with NSMCE1 was only mildly affected."

Yeast two-hybrid interaction mapping of the recurrent patient allele.

PMID:27427983 SUPPORT In Vitro

"NSMCE3 levels in both patient fibroblasts were dramatically reduced to levels that were below the level of detection in our assay."

Loss of detectable NSMCE3 protein in fibroblasts from both kindreds.

PMID:26446992 SUPPORT INDIRECT In Vitro

"Here we present evidence that the NSE1/NSE3/NSE4 sub-complex of SMC5/6 binds to double-stranded DNA without any preference for DNA-replication/recombination intermediates."

Establishes the double-stranded DNA binding activity of the module NSE3 belongs to; this study used recombinant proteins and fission yeast, not patient alleles.

+ 1 more reference

SMC5/6 Complex Destabilization

In patient fibroblasts from both kindreds SMC5 and SMC6 protein levels are significantly reduced along with NSMCE3, and p.Leu264Phe NSMCE3 is poorly incorporated into the native complex. The destabilization is much more severe than that caused by the truncating NSMCE2 allele of the related primordial dwarfism syndrome.

SMC5/6 destabilization causes lung injury independently of the immune defect

fibroblast CL:0000057

NSMCE3 hgnc:7677

SMC5/6 complex GO:0030915

Downstream

Defective Homologous Recombination Repair The SMC5/6 complex resolves recombination intermediates; its destabilization impairs double-strand break repair by homologous recombination while sparing nonhomologous end joining.

Impaired Recovery from Replication Stress Loss of SMC5/6 function prevents restart of DNA replication after a hydroxyurea block, a defect shared with NSMCE2-deficient cells.

Progressive Diffuse Alveolar Damage and Interstitial Lung Injury Lung injury that develops without preceding infection and with normal immune studies suggests a route from SMC5/6 loss to alveolar damage that does not pass through the immune defect. The cell type and intermediate steps are unknown; the founding authors speculated that loss of the NSMCE3-NSMCE4 interface specifically underlies the pulmonary phenotype.

Failure to thrive Failure to thrive precedes the lung disease and is present in nearly all patients; no source traces its mechanism. The founding authors attribute the more severe growth impairment in the compound heterozygous siblings to the more damaging p.Pro209Leu allele.

Feeding difficulties Reported from early infancy; mechanism not studied.

Small for gestational age Prenatal growth restriction in some patients; mechanism not studied.

Motor delay Mild motor delay in infancy; mechanism not studied.

Axial hypotonia Reported in the founding kindred; mechanism not studied.

Eczema Reported in the founding kindred; mechanism not studied.

Hepatomegaly Reported in two patients of the 2021 series; the authors describe its etiology as unknown.

Abnormal glucose homeostasis Hypo- and hyperglycemia in several patients; the authors consider both poor intake or critical illness and a possible SMC5/6 role in insulin metabolism.

Show evidence (2 references)

PMID:27427983 SUPPORT In Vitro

"In addition to NSMCE3, levels of the complex subunits SMC5 and SMC6 were also significantly reduced, indicating that the stability of the SMC5/6 protein complex is compromised in affected individuals of both kindreds"

Reduced SMC5 and SMC6 in patient fibroblasts from both families.

PMID:27427983 SUPPORT In Vitro

"Consistent with the destabilization of the complex seen in patient cells, the Leu264Phe variant showed reduced incorporation into the native SMC5/6 complex"

Reduced assembly of the mutant subunit into the endogenous complex in U2OS cells.

Defective Homologous Recombination Repair

Patient fibroblasts repair double-strand breaks normally in G1 (nonhomologous end joining intact) but, like BRCA2-deficient cells, fail to complete the slow repair fraction in G2 that depends on homologous recombination, and they are modestly hypersensitive to agents producing different types of DNA damage.

fibroblast CL:0000057

double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED

Downstream

Chromosomal Instability Unrepaired recombination intermediates and breaks give rise to chromosome breakage and rearrangement.

Increased sensitivity to ionizing radiation An HR defect leaves cells unable to repair a fraction of radiation-induced double-strand breaks.

Combined T and B Cell Dysfunction The authors attribute the lymphocyte proliferation defect to the HR defect. T cell loss could alternatively reflect increased apoptosis or reduced thymic output. V(D)J recombination, which depends on NHEJ, appears intact.

Show evidence (2 references)

PMID:27427983 SUPPORT In Vitro

"Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination."

Summary of the cellular phenotype including the HR defect.

PMID:27427983 SUPPORT In Vitro

"showed that repair kinetics in G1 cells were unaffected, consistent with proficient nonhomologous end joining (NHEJ)"

Shows the repair defect is restricted to HR, with NHEJ preserved.

Impaired Recovery from Replication Stress

After release from a hydroxyurea block, DNA replication recovers fully in control fibroblasts but not in patient fibroblasts, although similar fractions of cells arrest in S phase. Wild-type NSMCE3 restores recovery and the p.Leu264Phe protein does not. This was the most pronounced cellular defect.

fibroblast CL:0000057

replication fork processing GO:0031297 ↓ DECREASED

Downstream

Chromosomal Instability Stalled forks that are not rescued by HR-dependent restart are a recognised source of breaks, which would contribute to micronuclei and chromosome rearrangement; this step was not measured directly in patient cells.

Show evidence (2 references)

PMID:27427983 SUPPORT In Vitro

"The defect was restored by expression of normal NSMCE3 protein but not with the mutant protein (p.Leu264Phe), thus confirming that the replication recovery defect results from the NSMCE3 mutation"

Complementation shows the replication-recovery defect is caused by the patient allele.

PMID:27427983 SUPPORT In Vitro

"Consistently, in multiple experiments, the most dramatically altered response was seen in response to hydroxyurea (HU), a DNA replication inhibitor."

Replication stress is the most strongly affected response in patient cells.

Chromosomal Instability

Patient cells show stochastic chromosome rearrangements, chromosome breaks and de novo supernumerary marker chromosomes in lymphocytes, and micronuclei in about 20% of fibroblasts, a level similar to ATM-deficient cells. Array CGH of blood DNA shows no gains or losses, consistent with stochastic rather than clonal imbalances. A blood karyotype can be normal outside acute illness.

lymphocyte CL:0000542 fibroblast CL:0000057

Downstream

Chromosome breakage The cytogenetic readout of the instability.

Show evidence (2 references)

PMID:27427983 SUPPORT In Vitro

"Approximately 20% of cells contained micronuclei, which is similar to levels seen in ATM fibroblasts (Figure 3A) and to cells with mutations in NSMCE2, which encodes another component of the SMC5/6 complex (10)."

Quantifies micronucleus formation in patient fibroblasts.

PMID:27427983 SUPPORT Human Clinical

"Karyotyping of cultured peripheral lymphocytes drawn either before (individual A) or during illness (individual B) revealed multiple de novo supernumerary marker chromosomes with or without additional de novo chromosome rearrangements"

Clinical cytogenetic finding in patient lymphocytes.

Combined T and B Cell Dysfunction

In the founding kindreds T cell numbers were low, recall-antigen T cell proliferation absent or decreased, and specific antibody responses to vaccination poor, while B cell numbers and IgG and IgA were normal and IgM raised; thymic hypo- or aplasia was found in two patients. The immune defect is variable: most patients of the later Dutch series had normal T cell counts and proliferation and no recurrent infections. Normal B cell counts argue against a V(D)J recombination defect.

Viral pneumonia in combined immunodeficiency triggers the lung injury

T cell CL:0000084 B cell CL:0000236

T cell proliferation GO:0042098 ↓ DECREASED

Downstream

Combined immunodeficiency The clinical immunological diagnosis in the founding patients.

Decreased total T cell count Low T lymphocyte numbers in the founding kindreds.

Decreased antigen-specific T cell proliferation Absent or reduced proliferation to recall antigens.

Decreased specific antibody response to vaccination Poor specific antibody responses despite normal B cell counts.

Increased circulating IgM concentration Raised IgM with normal IgG and IgA; mechanism not studied.

Hypoplasia of the thymus Thymic hypo- or aplasia fits the low T cell counts, but whether it is a cause or a consequence of the T cell defect is not established.

Recurrent viral pneumonia Impaired adaptive immunity plausibly increases susceptibility to respiratory viral infection in the patients who have it; the later series had no infections.

Progressive Diffuse Alveolar Damage and Interstitial Lung Injury The original model: viral pneumonia in an immunodeficient infant triggers progressive, irreversible lung damage. Contested by the occurrence of the same fatal lung course in patients with normal immune studies and no infection.

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"This is consistent with the laboratory evaluations excluding SCID, but instead pointing to a distinct, combined T and B cell immunodeficiency."

Characterizes the immune defect as a non-SCID combined T and B cell immunodeficiency.

PMID:33741030 SUPPORT Human Clinical

"Altogether, subtle immunodeficiency in B- and T lymphocytes can be part of LICS but is not observed in all patients."

Establishes that the immune defect is variable rather than obligate.

Progressive Diffuse Alveolar Damage and Interstitial Lung Injury

The defining and fatal lesion. Lung biopsy and autopsy show diffuse alveolar damage with hyaline membranes, interstitial pneumonitis with lymphocyte-rich infiltrates, organizing pneumonia (including acute fibrinoid and organizing pneumonia), metaplastic squamous alveolar epithelium, lobular fibrosis and remodeling, and bronchiolitis obliterans, usually without evidence of active infection. Air leak (pneumomediastinum, pneumothorax, subcutaneous emphysema) complicates the course. Macrophage activation syndrome was not found. The authors attribute the failure of lung transplantation to the systemic nature of the disorder.

pulmonary alveolar epithelial cell CL:0000322

Downstream

Acute respiratory distress syndrome Clinical presentation of the diffuse alveolar injury.

Diffuse alveolar damage Histopathological hallmark.

Interstitial pneumonitis Interstitial inflammatory component.

Organizing pneumonia Organizing phase of the alveolar injury.

Pulmonary fibrosis Fibrotic remodeling of the injured lung.

Bronchiolitis obliterans Small-airway obliteration seen at autopsy.

Pneumomediastinum Air leak complicating the injured, often mechanically ventilated lung.

Pneumothorax Air leak complicating the injured lung.

Subcutaneous emphysema Extension of air leak into soft tissue.

Respiratory failure Progressive respiratory failure is the usual cause of death.

Clubbing Seen in the one patient with a chronic pulmonary course.

Show evidence (3 references)

PMID:33741030 SUPPORT Human Clinical

"Autopsy showed prolonged diffuse alveolar damage (DAD) as seen in the advanced stage of acute severe interstitial pneumonitis (IP) or pediatric acute respiratory distress syndrome (PARDS) without signs of infection"

Autopsy pathology of the lung lesion, without infection.

PMID:27427983 SUPPORT Human Clinical

"The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."

Autopsy pathology in a founding US patient.

PMID:33741030 SUPPORT Human Clinical

"During the disease periods where patients suffered from progressive and fatal pulmonary diseases, we found no evidence for macrophage activation syndrome (MAS)."

Argues against macrophage activation syndrome as the driver of the lung injury.

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Pathograph

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Phenotypes

28

Blood 3

Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Immunological analysis in individuals A and B showed that the numbers of T lymphocytes were low, but B lymphocytes and immunoglobulins were normal (except for increased IgM)."

Low T cell numbers with preserved B cells in the founding sisters.

PMID:27427983 SUPPORT Human Clinical

"Both affected individuals, C and D, showed diminished T cell percentage and an increased B cell percentage around 13 months of age"

Reduced T cell fraction in the founding US siblings.

Decreased antigen-specific T cell proliferation HP:0031402

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"T lymphocyte proliferation after stimulation with recall antigens was absent or decreased"

Absent or reduced recall-antigen T cell proliferation.

Increased circulating IgM concentration Increased circulating IgM level HP:0003496

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Immunological analysis in individuals A and B showed that the numbers of T lymphocytes were low, but B lymphocytes and immunoglobulins were normal (except for increased IgM)."

Raised IgM with otherwise normal immunoglobulins.

Cardiovascular 1

Hypoplasia of the thymus HP:0000778

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The decreased T cell counts could alternatively be indicative of increased apoptosis or defective thymic output, which could well fit the thymic hypo- and aplasia observed in patients A and D"

Thymic hypo- or aplasia in two founding patients.

Digestive 2

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Patients C, D and E suffered from feeding problems mainly vomiting, starting from birth."

Feeding problems from birth in three siblings.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"In addition, in two patients (B and E), hepatomegaly was noted."

Hepatomegaly in two of five patients of the later series.

Immune 5

Eczema Eczematoid dermatitis HP:0000964

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."

Eczema in the founding Dutch sisters.

Recurrent viral pneumonia HP:0033214

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"died at the ages of 12 and 14 months, respectively, due to severe progressive irreversible lung damage following multiple virus-induced pneumonia episodes"

Repeated viral pneumonia preceding fatal lung disease in the founding sisters.

PMID:33741030 SUPPORT Human Clinical

"In contrast to the previously reported patients, none of the patients reported in this paper had recurrent infections."

Shows the feature is variable, absent in the later series.

Acute respiratory distress syndrome HP:0033677

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"At 14 months of age, he developed progressive, severe PARDS following infectious pneumonia that led to his death."

Fatal pediatric ARDS in a founding US patient.

PMID:33741030 SUPPORT Human Clinical

"Autopsy showed prolonged diffuse alveolar damage (DAD) as seen in the advanced stage of acute severe interstitial pneumonitis (IP) or pediatric acute respiratory distress syndrome (PARDS) without signs of infection"

ARDS-stage alveolar damage without infection in a patient of the later series.

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency."

Combined immunodeficiency in the four founding patients.

Decreased specific antibody response to vaccination HP:0032140

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Several specific antibody responses after vaccination were low"

Low specific vaccine antibody responses.

Integument 1

Subcutaneous emphysema HP:6001021

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Chest X-ray on admission showed bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema."

Subcutaneous emphysema on admission chest X-ray.

Limbs 1

Clubbing HP:0001217

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Physical findings showed severe FTT, tachypnea and hypoxemia, a prominent sternum, clubbing of fingers and toes, bilateral rales on auscultation of the lungs and severe respiratory distress without signs of respiratory infection."

Clubbing in the long-surviving patient.

Metabolism 1

Abnormal glucose homeostasis HP:0011014

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Abnormalities in glucose homeostasis were noted in three patients (patient B, C and E), similar to two previously reported patients [1]."

Glucose abnormalities in five reported patients in total.

Musculoskeletal 1

Axial hypotonia HP:0008936

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."

Axial hypotonia in the founding Dutch sisters.

Nervous System 1

Motor delay HP:0001270

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Features of early onset FTT, including feeding difficulties and delayed motor milestones were present in all patients except patient E."

Delayed motor milestones in four of five patients.

Respiratory 7

Diffuse alveolar damage HP:0033006

Show evidence (2 references)

PMID:33741030 SUPPORT Human Clinical

"Lung biopsy showed severe diffuse IP with DAD."

Biopsy-proven diffuse alveolar damage.

PMID:33741030 SUPPORT Human Clinical

"Post mortem analysis revealed severe DAD with partial organization, presently called acute fibrinoid and organizing pneumonia (AFOP), with iron-laden macrophages without signs of infection."

Autopsy-proven diffuse alveolar damage in a second patient.

Interstitial pneumonitis HP:0006515

Show evidence (2 references)

PMID:33741030 SUPPORT Human Clinical

"Lung biopsy showed IP and extensive DAD."

Biopsy-proven interstitial pneumonitis.

PMID:27427983 SUPPORT Human Clinical

"Lung biopsy showed patchy acute interstitial infiltrates with lymphocyte predominance"

Lymphocyte-predominant interstitial infiltrates in a founding US patient.

Organizing pneumonia HP:0033670

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The histopathology of her explanted lungs revealed end-stage lung disease due to organizing pneumonia with extensive lobular remodeling"

Organizing pneumonia in the explanted lungs.

Pulmonary fibrosis HP:0002206

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."

Extensive lobular fibrosis at autopsy.

Bronchiolitis obliterans HP:0011946

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."

Bronchiolitis obliterans at autopsy in one patient.

Pneumothorax HP:0002107

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"their pulmonary status was complicated by pneumomediastinum, pneumothorax, and subcutaneous emphysema"

Pneumothorax in the founding Dutch sisters.

PMID:33741030 SUPPORT Human Clinical

"Despite invasive mechanical ventilation and treatment with dexamethasone, respiratory failure was progressive with bilateral pneumothorax and pneumomediastinum."

Bilateral pneumothorax in a patient of the later series.

Respiratory failure HP:0002878

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Despite treatment with methylprednisolone he died at the age of 11 months of severe progressive respiratory failure."

Fatal progressive respiratory failure.

Thoracic Cavity 1

Pneumomediastinum HP:0025421

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"their pulmonary status was complicated by pneumomediastinum, pneumothorax, and subcutaneous emphysema"

Air-leak complications in the founding Dutch sisters.

PMID:33741030 SUPPORT Human Clinical

"Chest X-ray on admission showed bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema."

The same air-leak triad in a patient of the later series.

Cellular 2

Chromosome breakage HP:0040012

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Lymphocytes of affected individuals showed increased chromosomal breakage, and fibroblasts were sensitive to DNA-damaging agents."

Increased chromosome breakage in patient lymphocytes.

PMID:27427983 SUPPORT Human Clinical

"Peripheral blood karyotype in lymphocytes of individual C at 6 months of age and when not acutely ill showed a normal (46,XY) karyotype, and in individual D breaks at 3p13~14 were identified in 2 of 28 examined cells."

Breaks in one sibling, normal karyotype when well in the other.

Increased sensitivity to ionizing radiation HP:0011133

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"A clinical radiosensitivity assay of lymphocytes (21) from individual D demonstrated increased sensitivity to 1 Gy of ionizing radiation"

Clinical lymphocyte radiosensitivity comparable to ataxia telangiectasia.

Growth 2

Failure to thrive HP:0001508

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."

Failure to thrive in the founding Dutch sisters before lung disease.

PMID:33741030 SUPPORT Human Clinical

"Patient C had FTT from birth."

Failure to thrive from birth in a patient of the later series.

Small for gestational age HP:0001518

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"The first male child of Family 1 (patient A) was born small for gestational age (SGA)."

SGA birth in a patient of the later series.

🧬

Genetic Associations

1

NSMCE3 (Causal biallelic missense variants that destabilize NSMCE3 and the SMC5/6 complex. Two alleles are reported, the recurrent c.790C>T (p.Leu264Phe) and p.Pro209Leu, both in the C-terminal winged-helix region that contacts NSMCE4.)

Gene: NSMCE3 hgnc:7677 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation."

Identifies NSMCE3 as the disease gene.

PMID:33741030 SUPPORT Human Clinical

"Targeted genetic testing revealed homozygosity for the NSMCE3 (NM_138704.3):c.790C > T mutation."

Independent confirmation in a further kindred.

🔬

Variants

2

NSMCE3 c.790C>T (p.Leu264Phe) Likely Pathogenic

Gene: NSMCE3 hgnc:7677 single nucleotide variant

Recurrent missense variant in the winged-helix B extension of NSMCE3 (rs199905054), found homozygous in both Dutch kindreds and in trans with p.Pro209Leu in the US kindred. It abolishes NSMCE4 binding, mildly weakens NSMCE1 binding and reduces incorporation into the SMC5/6 complex, and it fails to rescue the replication-recovery defect. It was seen heterozygous in 3 of 500 unrelated Dutch individuals.

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The likely pathogenic variant results in a p.Leu264Phe missense change in NSMCE3 (NM_138704.3:c.790C>T) in a conserved region of the protein."

Identifies the recurrent allele and the authors' classification.

NSMCE3 p.Pro209Leu Likely Pathogenic

Gene: NSMCE3 hgnc:7677 single nucleotide variant

Missense variant in the NSMCE3 winged-helix B domain, at the end of the preceding helical element; paternally inherited in the US kindred in trans with p.Leu264Phe and absent from ExAC. It abolishes NSMCE4 binding, drastically reduces NSMCE1 binding and makes the recombinant protein prone to C-terminal truncation. The cDNA description is not given in the cited text.

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"Two missense and likely pathogenic variants in NSMCE3 were found (Figure 1M), consisting of a maternally inherited p.Leu264Phe (NM_138704.3:c.790C>T) change (identical to individuals A and B) and a paternally derived G-to-A substitution resulting in a p.Pro209Leu change."

Identifies the second allele in the compound heterozygous siblings.

PMID:27427983 SUPPORT In Vitro

"The Pro209Leu mutation of the affected individuals C and D, as well as abolishing the NSMCE4 interaction, also drastically reduced the NSMCE1 interaction"

Functional effect of the allele on complex interactions.

💊

Medical Actions

4

Allogeneic hematopoietic stem cell transplantation

Action: allogeneic hematopoietic stem cell transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Platform: Cell therapy

Attempted in one mildly symptomatic infant on the premise that immunodeficiency drives the lung disease: unrelated cord blood after reduced-intensity conditioning with fludarabine and cyclophosphamide at 10 months. The graft was rejected and the child died of respiratory failure at 11 months with diffuse alveolar damage without infection. Not curative in the single reported attempt.

Show evidence (1 reference)

PMID:33741030 REFUTE Human Clinical

"Hematopoietic stem-cell transplantation failed to cure another patient."

The single reported HSCT did not prevent fatal disease.

Lung transplantation

Action: lung transplantation Ontology label: Lung Transplantation NCIT:C15274

Platform: Surgery

Performed once, at 15 months of age, for end-stage lung disease. The child later developed bone marrow failure and infections and died at 32 months. The later series considered lung transplantation not beneficial in LICS.

Show evidence (2 references)

PMID:27427983 SUPPORT Human Clinical

"She underwent cadaveric lung transplantation at 15 months of age because of severe pulmonary damage initially resembling PARDS."

Documents the single lung transplant performed.

PMID:33741030 REFUTE Human Clinical

"Lung transplantation was also shown not to be beneficial in LICS ... likely because of the underlying systemic nature of this disorder."

Authors' judgement that lung transplantation did not benefit the patient.

Systemic corticosteroids

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Agent: methylprednisolone CHEBI:6888

Platform: Small molecule

Methylprednisolone, dexamethasone or prednisolone, in one patient with azathioprine, cyclophosphamide and hydroxychloroquine, were given during the pulmonary crisis without halting progression.

Show evidence (2 references)

PMID:33741030 REFUTE Human Clinical

"He died at the age of 15 months, of severe respiratory distress despite maximal supportive care and treatment with methylprednisolone."

Fatal progression despite methylprednisolone.

PMID:33741030 REFUTE Human Clinical

"Treatment with oxygen, methylprednisolone pulse therapy followed by azathioprine, cyclophosphamide and hydroxychloroquine did not result in improvement."

No response to pulse steroids and immunosuppression in the chronic patient.

Genetic counseling and prenatal testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Recommended for affected families; prenatal testing was used in one family to confirm an unaffected pregnancy.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"In affected families, genetic counseling and prenatal testing should be offered."

Authors' recommendation.

🔬

Diagnosis

2

NSMCE3 molecular genetic testing (Biallelic pathogenic NSMCE3 variants confirm the diagnosis.)

Exome sequencing or targeted NSMCE3 sequencing identifies biallelic variants. Several patients were diagnosed only post mortem by reanalysis of stored DNA. The authors recommend considering NSMCE3 testing in children with unexplained rapid pulmonary failure after pneumonia, unexplained chronic pediatric lung disease, or early failure to thrive with motor delay.

exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:33741030 SUPPORT Human Clinical

"We further conclude that DNA analysis of NSMCE3 for LICS should be considered in patients with unexplained chronic pediatric pulmonary disease"

Recommendation for NSMCE3 testing.

PMID:27427983 SUPPORT Human Clinical

"We recommend development of a clinical assay for the replication recovery defect and for NSMCE3 mutations and consideration of this disorder for children with unexplained, rapid pulmonary failure following multiple virus-induced pneumonias."

Founding authors' diagnostic recommendation.

Karyotype and radiosensitivity testing (Spontaneous chromosome breakage or radiosensitivity supports the diagnosis.)

Lymphocyte karyotyping may show chromosome breaks, rearrangements and supernumerary marker chromosomes, and lymphocyte or fibroblast assays show radiosensitivity. These are supportive, not specific, and a karyotype taken outside acute illness can be normal.

karyotyping NCIT:C16768

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"Clinical assays, such as karyotyping and IR sensitivity, could be abnormal and can be early indicators of the syndrome."

Cytogenetic and radiosensitivity assays as early indicators.

📈

Progression

3

Infantile failure to thrive and motor delay

Age: Birth to about 10 months

Feeding problems and failure to thrive start in early infancy, sometimes from birth, with mild motor delay; respiratory symptoms are absent or mild at this stage.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Features of early onset FTT, including feeding difficulties and delayed motor milestones were present in all patients except patient E."

Early-onset failure to thrive and motor delay as the first phase.

Acute fatal pulmonary decompensation

Age: About 10 to 14 months

Rapidly progressive pediatric ARDS with irreversible diffuse alveolar damage, usually fatal within weeks despite mechanical ventilation and corticosteroids.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"in addition to previously reported features of early onset (severe) FTT, (mild) motor developmental delay, and acute pulmonary disease around 10-14 months of age with irreversible DAD"

States the typical age window of the acute pulmonary phase.

Chronic pulmonary course

Age: Up to 6.5 years

One patient had interstitial lung disease from about 2 years of age, later with hypoxemia and digital clubbing, and died of respiratory failure at 6.5 years.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"This relatively long survival of a patient with LICS is of clinical importance as it indicates that, apart from the acute and fatal course presenting around 10-14 months, a more chronic form exists as well."

Establishes a chronic course alongside the acute infantile one.

📊

Prevalence

2

Worldwide

Cases In Literature

Nine patients had been reported by 2021 (four in the founding report and five in the Dutch follow-up series, all homozygous or compound heterozygous for NSMCE3 missense variants). A further single case, an 11-year-old boy with fatal lung disease, was reported in 2025 (PMID:40728043); that report has no abstract in PubMed and is not quoted here.

Show evidence (1 reference)

PMID:33741030 SUPPORT Human Clinical

"Until now, 9 patients with LICS were reported."

Literature case count as of the 2021 series.

Netherlands (Genome of the Netherlands, 500 unrelated individuals)

Carrier Frequency 600.0 per 100,000

Carrier frequency of the single recurrent NSMCE3 c.790C>T (p.Leu264Phe) allele, not of all pathogenic NSMCE3 alleles: observed heterozygous 3 times in 500 unrelated Dutch individuals (allele frequency 0.003). All five patients of the 2021 series were homozygous for this allele. The ExAC European heterozygous allele frequency was far lower (4.5 x 10^-5).

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"In the Genome of the Netherlands (GoNL) study, the variant has been observed in the heterozygous state 3 times in 500 unrelated individuals, indicating an allele frequency of 0.003 in the Netherlands (19), showing that the variant is not uncommon in the Dutch population."

Source of the Dutch carrier count for c.790C>T.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome:

Nijmegen breakage syndrome MONDO:0009623

Overlapping Features Chromosome breakage syndrome with combined immunodeficiency and radiosensitivity. The founding authors contrast it with LICS on B cell counts and V(D)J recombination, which are defective in NBS and normal in LICS.

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The affected individuals share some clinical features with individuals with Nijmegen breakage syndrome (NBS) and AT chromosomal breakage syndrome"

Clinical overlap noted by the founding authors.

Ataxia telangiectasia MONDO:0008840

Overlapping Features Shares radiosensitivity, chromosome instability, thymic hypoplasia and combined immunodeficiency, and interstitial lung disease is described in it. In LICS B cell counts are normal and V(D)J recombination appears intact, and ATM protein was only partly reduced in a patient cell line.

Show evidence (1 reference)

PMID:27427983 SUPPORT Human Clinical

"The fact that in the 4 affected individuals B cell counts were normal indicates proper efflux from the bone marrow, which is defective in AT and NBS (40, 41)."

Distinguishing immunological feature from AT and NBS.

{ }

Source YAML

click to show

name: Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome
creation_date: "2026-10-12T14:48:06Z"
category: Mendelian
description: >-
  Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS; OMIM
  617241) is an ultra-rare autosomal recessive chromosome breakage syndrome caused
  by biallelic missense variants in NSMCE3 (also known as NDNL2), which encodes the
  MAGE-family NSE3 subunit of the SMC5/6 structural-maintenance-of-chromosomes
  complex. The patient missense alleles weaken NSMCE3 binding to NSMCE4 and
  NSMCE1 and destabilize the whole SMC5/6 complex, so that patient cells show
  defective homologous recombination, failure to recover from replication stress,
  micronuclei, stochastic chromosome rearrangements and radiosensitivity.

  Affected infants have failure to thrive, feeding difficulties and mild motor
  delay, and then, typically between about 10 and 14 months of age, develop rapidly
  progressive, irreversible lung disease presenting as pediatric acute respiratory
  distress syndrome with diffuse alveolar damage, interstitial pneumonitis and
  fibrosis, complicated by pneumomediastinum and pneumothorax; nearly all reported
  patients died in early childhood, one surviving to 6.5 years with a more chronic
  course. The founding report described combined T and B cell immunodeficiency and
  lung decompensation after viral pneumonia, but a later series of five patients
  had normal or near-normal immune studies and no preceding infection, so whether
  the immune defect drives the lung injury is unresolved. Neither haematopoietic
  stem cell transplantation nor lung transplantation has been curative.
disease_term:
  preferred_term: lung disease, immunodeficiency, and chromosome breakage syndrome
  term:
    id: MONDO:0014984
    label: lung disease, immunodeficiency, and chromosome breakage syndrome;
synonyms:
- LICS
- NSMCE3 deficiency
- NSMCE3 chromosomal breakage syndrome
- lung disease immunodeficiency and chromosome breakage syndrome
parents:
- hereditary disease
- chromosomal instability syndrome
- DNA repair disorder
- Inborn error of immunity
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood."
      explanation: >-
        Defines LICS as a monogenic autosomal recessive chromosome breakage
        syndrome, which places it in the genetics Part.
  - classification_value: RESPIRATORY
    evidence:
    - reference: PMID:33741030
      reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We propose to categorize LICS as 'specific condition of undefined etiology', one of the 9 categories of chILD classification [12]."
      explanation: >-
        The lung disease is the presenting problem and the cause of death, and the
        authors place LICS within the childhood interstitial lung disease
        classification.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS 2024 Table 2 ("CIDs with associated or syndromic features"), subtable 2
      "DNA repair defects other than those listed in Table 1", row "NSMCE3
      deficiency". The immune phenotype is variable: the later Dutch series reported
      normal T cell numbers and proliferation in most patients.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "NSMCE3 deficiency | NSMCE3 | AR | 608243 | Decreased number, poor responses to mitogens and antigens | Normal | Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS | Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity"
      explanation: >-
        The IUIS 2024 classification row for NSMCE3 deficiency in the DNA repair
        defect subtable of the syndromic combined immunodeficiency table.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Affected children are homozygous or compound heterozygous for NSMCE3 missense
    variants and their parents are healthy heterozygous carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous and compound heterozygous mutations were found in 2 independent kindreds, in which 4 children died in early childhood after developing rapidly progressive pulmonary disease following viral pneumonia."
    explanation: Biallelic variants in affected children of two unrelated kindreds.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal recessive lung disease immuno-deficiency and chromosome breakage syndrome (LICS), caused by missense mutations in NSMCE3, was first described in 2016 [1]."
    explanation: Independent series restating the autosomal recessive mode of inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    Nine patients had been reported by 2021 (four in the founding report and five
    in the Dutch follow-up series, all homozygous or compound heterozygous for
    NSMCE3 missense variants). A further single case, an 11-year-old boy with fatal
    lung disease, was reported in 2025 (PMID:40728043); that report has no
    abstract in PubMed and is not quoted here.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Until now, 9 patients with LICS were reported."
    explanation: Literature case count as of the 2021 series.
- population: Netherlands (Genome of the Netherlands, 500 unrelated individuals)
  measure_type: CARRIER_FREQUENCY
  rate_per_100000: 600.0
  notes: >-
    Carrier frequency of the single recurrent NSMCE3 c.790C>T (p.Leu264Phe) allele,
    not of all pathogenic NSMCE3 alleles: observed heterozygous 3 times in 500
    unrelated Dutch individuals (allele frequency 0.003). All five patients of the
    2021 series were homozygous for this allele. The ExAC European heterozygous
    allele frequency was far lower (4.5 x 10^-5).
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the Genome of the Netherlands (GoNL) study, the variant has been observed in the heterozygous state 3 times in 500 unrelated individuals, indicating an allele frequency of 0.003 in the Netherlands (19), showing that the variant is not uncommon in the Dutch population."
    explanation: Source of the Dutch carrier count for c.790C>T.
progression:
- phase: Infantile failure to thrive and motor delay
  age_range: Birth to about 10 months
  notes: >-
    Feeding problems and failure to thrive start in early infancy, sometimes from
    birth, with mild motor delay; respiratory symptoms are absent or mild at this
    stage.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features of early onset FTT, including feeding difficulties and delayed motor milestones were present in all patients except patient E."
    explanation: Early-onset failure to thrive and motor delay as the first phase.
- phase: Acute fatal pulmonary decompensation
  age_range: About 10 to 14 months
  notes: >-
    Rapidly progressive pediatric ARDS with irreversible diffuse alveolar damage,
    usually fatal within weeks despite mechanical ventilation and corticosteroids.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to previously reported features of early onset (severe) FTT, (mild) motor developmental delay, and acute pulmonary disease around 10-14 months of age with irreversible DAD"
    explanation: States the typical age window of the acute pulmonary phase.
- phase: Chronic pulmonary course
  age_range: Up to 6.5 years
  notes: >-
    One patient had interstitial lung disease from about 2 years of age, later with
    hypoxemia and digital clubbing, and died of respiratory failure at 6.5 years.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This relatively long survival of a patient with LICS is of clinical importance as it indicates that, apart from the acute and fatal course presenting around 10-14 months, a more chronic form exists as well."
    explanation: Establishes a chronic course alongside the acute infantile one.
pathophysiology:
- name: NSMCE3 Missense Protein Destabilization
  biological_scale: MOLECULAR
  description: >-
    The patient missense variants sit in the C-terminal winged-helix B domain
    (p.Pro209Leu) and its extension (p.Leu264Phe) of NSMCE3. Both abolish binding
    to NSMCE4, and p.Pro209Leu also strongly reduces binding to NSMCE1 and makes the
    recombinant protein prone to C-terminal truncation. Endogenous NSMCE3 falls
    below the detection limit in patient fibroblasts; because loss of other SMC5/6
    subunits is embryonic lethal in mice, the authors infer that some NSMCE3
    persists at low level.
  genetic_context:
    gene:
      preferred_term: NSMCE3
      term:
        id: hgnc:7677
        label: NSMCE3
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Biallelic missense variants, homozygous p.Leu264Phe or compound heterozygous
      p.Leu264Phe/p.Pro209Leu. Partial rather than complete loss of function is the
      authors' inference from the embryonic lethality of SMC6 and NSMCE2 loss in
      mice; residual NSMCE3 was not directly measured.
  molecular_functions:
  - preferred_term: double-stranded DNA binding by the NSE1/NSE3/NSE4 module
    modifier: DECREASED
    term:
      id: GO:0003690
      label: double-stranded DNA binding
    description: >-
      NSE3 binds double-stranded DNA through its C-terminal winged-helix B domain,
      the domain carrying both patient variants, and this binding is needed to load
      SMC5/6 onto chromatin in fission yeast. Reduced DNA binding by the patient
      alleles is inferred from their location and from the loss of the module, not
      measured directly.
  genes:
  - preferred_term: NSMCE3
    term:
      id: hgnc:7677
      label: NSMCE3
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Leu264Phe mutation of the affected individuals A-D abolished binding of NSMCE3 to NSMCE4, while its interaction with NSMCE1 was only mildly affected."
    explanation: Yeast two-hybrid interaction mapping of the recurrent patient allele.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NSMCE3 levels in both patient fibroblasts were dramatically reduced to levels that were below the level of detection in our assay."
    explanation: Loss of detectable NSMCE3 protein in fibroblasts from both kindreds.
  - reference: PMID:26446992
    reference_title: "Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Here we present evidence that the NSE1/NSE3/NSE4 sub-complex of SMC5/6 binds to double-stranded DNA without any preference for DNA-replication/recombination intermediates."
    explanation: >-
      Establishes the double-stranded DNA binding activity of the module NSE3
      belongs to; this study used recombinant proteins and fission yeast, not
      patient alleles.
  - reference: PMID:26446992
    reference_title: "Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "C-terminal part of NSE3 contains the putative DNA-binding winged helix B (WH-B) domain with conserved basic residues."
    explanation: >-
      Places the DNA-binding surface in the winged-helix B domain, where both LICS
      missense variants lie.
  downstream:
  - target: SMC5/6 Complex Destabilization
    causal_link_type: DIRECT
    description: >-
      Loss of the NSMCE3-NSMCE4 interface weakens the subcomplex that bridges the
      SMC5 and SMC6 subunits, so the complex as a whole is destabilized.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together these data show that the identified missense variants in NSMCE3 destabilize NSMCE3 and the SMC5/6 complex."
      explanation: Links the NSMCE3 variants directly to destabilization of the complex.
- name: SMC5/6 Complex Destabilization
  biological_scale: MOLECULAR
  description: >-
    In patient fibroblasts from both kindreds SMC5 and SMC6 protein levels are
    significantly reduced along with NSMCE3, and p.Leu264Phe NSMCE3 is poorly
    incorporated into the native complex. The destabilization is much more severe
    than that caused by the truncating NSMCE2 allele of the related primordial
    dwarfism syndrome.
  genes:
  - preferred_term: NSMCE3
    term:
      id: hgnc:7677
      label: NSMCE3
  protein_complexes:
  - preferred_term: SMC5/6 complex
    term:
      id: GO:0030915
      label: Smc5-Smc6 complex
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In addition to NSMCE3, levels of the complex subunits SMC5 and SMC6 were also significantly reduced, indicating that the stability of the SMC5/6 protein complex is compromised in affected individuals of both kindreds"
    explanation: Reduced SMC5 and SMC6 in patient fibroblasts from both families.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistent with the destabilization of the complex seen in patient cells, the Leu264Phe variant showed reduced incorporation into the native SMC5/6 complex"
    explanation: Reduced assembly of the mutant subunit into the endogenous complex in U2OS cells.
  downstream:
  - target: Defective Homologous Recombination Repair
    causal_link_type: DIRECT
    description: >-
      The SMC5/6 complex resolves recombination intermediates; its destabilization
      impairs double-strand break repair by homologous recombination while sparing
      nonhomologous end joining.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In cells from affected individual B, the destabilization of the SMC5/6 complex resulted in defective DNA repair by HR but not by NHEJ."
      explanation: Direct statement of the complex-to-HR-defect link in patient cells.
  - target: Impaired Recovery from Replication Stress
    causal_link_type: DIRECT
    description: >-
      Loss of SMC5/6 function prevents restart of DNA replication after a
      hydroxyurea block, a defect shared with NSMCE2-deficient cells.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The lack of recovery from replication stress is also seen in cells mutated in NSMCE2 (10), showing it to be a common consequence of misregulation of the SMC5/6 complex."
      explanation: Places the replication-recovery defect downstream of SMC5/6 misregulation.
  - target: Progressive Diffuse Alveolar Damage and Interstitial Lung Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - intrinsic_systemic_lung_disease
    description: >-
      Lung injury that develops without preceding infection and with normal immune
      studies suggests a route from SMC5/6 loss to alveolar damage that does not
      pass through the immune defect. The cell type and intermediate steps are
      unknown; the founding authors speculated that loss of the NSMCE3-NSMCE4
      interface specifically underlies the pulmonary phenotype.
    evidence:
    - reference: PMID:33741030
      reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings suggest that the immunological abnormalities can be limited and do not fully explain the LICS phenotype."
      explanation: Clinical argument that the lung disease is not fully explained by the immune defect.
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As both mutations in NSMCE3 disrupt the interaction with NSMCE4, we speculate that such mutations specifically result in the pulmonary phenotype that we have observed."
      explanation: The founding report's own speculation linking the specific molecular lesion to the lung phenotype.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure to thrive precedes the lung disease and is present in nearly all
      patients; no source traces its mechanism. The founding authors attribute the
      more severe growth impairment in the compound heterozygous siblings to the
      more damaging p.Pro209Leu allele.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported from early infancy; mechanism not studied.
  - target: Small for gestational age
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Prenatal growth restriction in some patients; mechanism not studied.
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mild motor delay in infancy; mechanism not studied.
  - target: Axial hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported in the founding kindred; mechanism not studied.
  - target: Eczema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported in the founding kindred; mechanism not studied.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported in two patients of the 2021 series; the authors describe its etiology as unknown.
  - target: Abnormal glucose homeostasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypo- and hyperglycemia in several patients; the authors consider both poor
      intake or critical illness and a possible SMC5/6 role in insulin metabolism.
- name: Defective Homologous Recombination Repair
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts repair double-strand breaks normally in G1 (nonhomologous
    end joining intact) but, like BRCA2-deficient cells, fail to complete the slow
    repair fraction in G2 that depends on homologous recombination, and they are
    modestly hypersensitive to agents producing different types of DNA damage.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    modifier: DECREASED
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination."
    explanation: Summary of the cellular phenotype including the HR defect.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "showed that repair kinetics in G1 cells were unaffected, consistent with proficient nonhomologous end joining (NHEJ)"
    explanation: Shows the repair defect is restricted to HR, with NHEJ preserved.
  downstream:
  - target: Chromosomal Instability
    causal_link_type: DIRECT
    description: Unrepaired recombination intermediates and breaks give rise to chromosome breakage and rearrangement.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lymphocytes of affected individuals showed increased chromosomal breakage, and fibroblasts were sensitive to DNA-damaging agents."
      explanation: Chromosome breakage alongside DNA-damage sensitivity in patient cells.
  - target: Increased sensitivity to ionizing radiation
    causal_link_type: DIRECT
    description: An HR defect leaves cells unable to repair a fraction of radiation-induced double-strand breaks.
  - target: Combined T and B Cell Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors attribute the lymphocyte proliferation defect to the HR defect.
      T cell loss could alternatively reflect increased apoptosis or reduced thymic
      output. V(D)J recombination, which depends on NHEJ, appears intact.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The underlying lymphocyte proliferation defect is consistent with the destabilization of the SMC5/6 complex seen in fibroblasts and consequential defect in HR (32)."
      explanation: >-
        Authors' proposed link from the HR defect to lymphocyte dysfunction,
        inferred from fibroblast data rather than shown in lymphocytes.
- name: Impaired Recovery from Replication Stress
  biological_scale: CELLULAR
  description: >-
    After release from a hydroxyurea block, DNA replication recovers fully in
    control fibroblasts but not in patient fibroblasts, although similar fractions
    of cells arrest in S phase. Wild-type NSMCE3 restores recovery and the
    p.Leu264Phe protein does not. This was the most pronounced cellular defect.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: replication fork processing
    modifier: DECREASED
    term:
      id: GO:0031297
      label: replication fork processing
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The defect was restored by expression of normal NSMCE3 protein but not with the mutant protein (p.Leu264Phe), thus confirming that the replication recovery defect results from the NSMCE3 mutation"
    explanation: Complementation shows the replication-recovery defect is caused by the patient allele.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistently, in multiple experiments, the most dramatically altered response was seen in response to hydroxyurea (HU), a DNA replication inhibitor."
    explanation: Replication stress is the most strongly affected response in patient cells.
  downstream:
  - target: Chromosomal Instability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Stalled forks that are not rescued by HR-dependent restart are a recognised
      source of breaks, which would contribute to micronuclei and chromosome
      rearrangement; this step was not measured directly in patient cells.
    evidence:
    - reference: PMID:27427983
      reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "HR is required to stabilize stalled forks and rescue replication (31)."
      explanation: Background statement linking HR to rescue of stalled replication forks.
- name: Chromosomal Instability
  biological_scale: CELLULAR
  description: >-
    Patient cells show stochastic chromosome rearrangements, chromosome breaks and
    de novo supernumerary marker chromosomes in lymphocytes, and micronuclei in
    about 20% of fibroblasts, a level similar to ATM-deficient cells. Array CGH of
    blood DNA shows no gains or losses, consistent with stochastic rather than
    clonal imbalances. A blood karyotype can be normal outside acute illness.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Approximately 20% of cells contained micronuclei, which is similar to levels seen in ATM fibroblasts (Figure 3A) and to cells with mutations in NSMCE2, which encodes another component of the SMC5/6 complex (10)."
    explanation: Quantifies micronucleus formation in patient fibroblasts.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Karyotyping of cultured peripheral lymphocytes drawn either before (individual A) or during illness (individual B) revealed multiple de novo supernumerary marker chromosomes with or without additional de novo chromosome rearrangements"
    explanation: Clinical cytogenetic finding in patient lymphocytes.
  downstream:
  - target: Chromosome breakage
    causal_link_type: DIRECT
    description: The cytogenetic readout of the instability.
- name: Combined T and B Cell Dysfunction
  biological_scale: CELLULAR
  description: >-
    In the founding kindreds T cell numbers were low, recall-antigen T cell
    proliferation absent or decreased, and specific antibody responses to
    vaccination poor, while B cell numbers and IgG and IgA were normal and IgM
    raised; thymic hypo- or aplasia was found in two patients. The immune defect is
    variable: most patients of the later Dutch series had normal T cell counts and
    proliferation and no recurrent infections. Normal B cell counts argue against a
    V(D)J recombination defect.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is consistent with the laboratory evaluations excluding SCID, but instead pointing to a distinct, combined T and B cell immunodeficiency."
    explanation: Characterizes the immune defect as a non-SCID combined T and B cell immunodeficiency.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, subtle immunodeficiency in B- and T lymphocytes can be part of LICS but is not observed in all patients."
    explanation: Establishes that the immune defect is variable rather than obligate.
  downstream:
  - target: Combined immunodeficiency
    causal_link_type: DIRECT
    description: The clinical immunological diagnosis in the founding patients.
  - target: Decreased total T cell count
    causal_link_type: DIRECT
    description: Low T lymphocyte numbers in the founding kindreds.
  - target: Decreased antigen-specific T cell proliferation
    causal_link_type: DIRECT
    description: Absent or reduced proliferation to recall antigens.
  - target: Decreased specific antibody response to vaccination
    causal_link_type: DIRECT
    description: Poor specific antibody responses despite normal B cell counts.
  - target: Increased circulating IgM concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Raised IgM with normal IgG and IgA; mechanism not studied.
  - target: Hypoplasia of the thymus
    causal_link_type: UNKNOWN
    description: >-
      Thymic hypo- or aplasia fits the low T cell counts, but whether it is a
      cause or a consequence of the T cell defect is not established.
  - target: Recurrent viral pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired adaptive immunity plausibly increases susceptibility to respiratory
      viral infection in the patients who have it; the later series had no
      infections.
  - target: Progressive Diffuse Alveolar Damage and Interstitial Lung Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - immunodeficiency_triggered_lung_injury
    description: >-
      The original model: viral pneumonia in an immunodeficient infant triggers
      progressive, irreversible lung damage. Contested by the occurrence of the same
      fatal lung course in patients with normal immune studies and no infection.
    evidence:
    - reference: PMID:33741030
      reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The hypothesis at that time was that the immunodeficiency was responsible for the rapid respiratory deterioration seen in patients with LICS."
      explanation: States the original immune-driven model of the lung disease.
    - reference: PMID:33741030
      reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "We further conclude that immunodeficiency is unlikely to cause the acute respiratory failure in LICS, as this course was also present in the patients with normal immunological evaluations as we now report."
      explanation: Five later patients developed the same fatal lung course with normal immune evaluations.
- name: Progressive Diffuse Alveolar Damage and Interstitial Lung Injury
  biological_scale: TISSUE
  description: >-
    The defining and fatal lesion. Lung biopsy and autopsy show diffuse alveolar
    damage with hyaline membranes, interstitial pneumonitis with lymphocyte-rich
    infiltrates, organizing pneumonia (including acute fibrinoid and organizing
    pneumonia), metaplastic squamous alveolar epithelium, lobular fibrosis and
    remodeling, and bronchiolitis obliterans, usually without evidence of active
    infection. Air leak (pneumomediastinum, pneumothorax, subcutaneous emphysema)
    complicates the course. Macrophage activation syndrome was not found. The
    authors attribute the failure of lung transplantation to the systemic nature of
    the disorder.
  cell_types:
  - preferred_term: pulmonary alveolar epithelial cell
    term:
      id: CL:0000322
      label: pulmonary alveolar epithelial cell
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy showed prolonged diffuse alveolar damage (DAD) as seen in the advanced stage of acute severe interstitial pneumonitis (IP) or pediatric acute respiratory distress syndrome (PARDS) without signs of infection"
    explanation: Autopsy pathology of the lung lesion, without infection.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."
    explanation: Autopsy pathology in a founding US patient.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the disease periods where patients suffered from progressive and fatal pulmonary diseases, we found no evidence for macrophage activation syndrome (MAS)."
    explanation: Argues against macrophage activation syndrome as the driver of the lung injury.
  downstream:
  - target: Acute respiratory distress syndrome
    causal_link_type: DIRECT
    description: Clinical presentation of the diffuse alveolar injury.
  - target: Diffuse alveolar damage
    causal_link_type: DIRECT
    description: Histopathological hallmark.
  - target: Interstitial pneumonitis
    causal_link_type: DIRECT
    description: Interstitial inflammatory component.
  - target: Organizing pneumonia
    causal_link_type: DIRECT
    description: Organizing phase of the alveolar injury.
  - target: Pulmonary fibrosis
    causal_link_type: DIRECT
    description: Fibrotic remodeling of the injured lung.
  - target: Bronchiolitis obliterans
    causal_link_type: DIRECT
    description: Small-airway obliteration seen at autopsy.
  - target: Pneumomediastinum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Air leak complicating the injured, often mechanically ventilated lung.
  - target: Pneumothorax
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Air leak complicating the injured lung.
  - target: Subcutaneous emphysema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Extension of air leak into soft tissue.
  - target: Respiratory failure
    causal_link_type: DIRECT
    description: Progressive respiratory failure is the usual cause of death.
  - target: Clubbing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Seen in the one patient with a chronic pulmonary course.
mechanistic_hypotheses:
- hypothesis_group_id: immunodeficiency_triggered_lung_injury
  hypothesis_label: Viral pneumonia in combined immunodeficiency triggers the lung injury
  status: ALTERNATIVE
  description: >-
    The founding report linked the lung disease to viral pneumonia in infants with
    a combined T and B cell defect. This motivated a trial of haematopoietic stem
    cell transplantation, which did not prevent fatal lung disease. Five later
    patients developed the same course without infection and with normal immune
    evaluations, so the immune defect is at most a contributing factor in some
    patients.
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder, designated LICS, which expands the spectrum of chromosomal breakage syndromes, is associated with progressive, severe PARDS following viral pneumonia, resulting in death in early childhood of the affected individuals described here."
    explanation: The founding report's association of the lung disease with preceding viral pneumonia.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, we present five recently identified LICS patients who developed fatal lung disease without signs of infection and who expressed a variable immunological phenotype."
    explanation: Fatal lung disease without infection argues against an obligatory infectious trigger.
- hypothesis_group_id: intrinsic_systemic_lung_disease
  hypothesis_label: SMC5/6 destabilization causes lung injury independently of the immune defect
  status: EMERGING
  description: >-
    The later series reframed LICS as a childhood interstitial lung disease of
    undefined etiology driven by the systemic SMC5/6 defect rather than by
    immunodeficiency. Candidate routes named in the literature, none tested in lung
    tissue, include a specific consequence of losing the NSMCE3-NSMCE4 interface,
    and loss of the SMC5/6 complex's role in silencing transcription from viral
    circular DNA genomes, which could permit exaggerated viral or inflammatory
    responses.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung transplantation was also shown not to be beneficial in LICS ... likely because of the underlying systemic nature of this disorder."
    explanation: Authors attribute treatment failure to a systemic, not purely immune, disease.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Data on the function of the SMC5/6 complex suggests it plays a role in prevention of transcription from viral circular DNA genomes and that it thereby has a suppressive role in the development of viral infections and inflammatory processes"
    explanation: >-
      Background statement of a candidate route; the cited work is on viral
      restriction in other systems, not on LICS lung tissue.
phenotypes:
- name: Failure to thrive
  category: Growth
  description: >-
    Early-onset failure to thrive, often severe and sometimes needing tube feeding,
    precedes the lung disease in almost all patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."
    explanation: Failure to thrive in the founding Dutch sisters before lung disease.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient C had FTT from birth."
    explanation: Failure to thrive from birth in a patient of the later series.
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients C, D and E suffered from feeding problems mainly vomiting, starting from birth."
    explanation: Feeding problems from birth in three siblings.
- name: Small for gestational age
  category: Growth
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first male child of Family 1 (patient A) was born small for gestational age (SGA)."
    explanation: SGA birth in a patient of the later series.
- name: Motor delay
  category: Neurological
  description: Mild delay of motor milestones; the long-surviving patient had normal motor development.
  phenotype_term:
    preferred_term: Delayed motor milestones
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features of early onset FTT, including feeding difficulties and delayed motor milestones were present in all patients except patient E."
    explanation: Delayed motor milestones in four of five patients.
- name: Axial hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."
    explanation: Axial hypotonia in the founding Dutch sisters.
- name: Eczema
  category: Dermatologic
  phenotype_term:
    preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prior to these episodes, the children experienced feeding difficulties, failure to thrive, weight loss, mild psychomotor retardation, axial hypotonia, increased infection susceptibility (due to distinct B and T cell abnormalities), and eczema."
    explanation: Eczema in the founding Dutch sisters.
- name: Recurrent viral pneumonia
  category: Infectious
  description: >-
    Multiple virus-induced pneumonias preceded fatal lung disease in the founding
    kindreds; no patient of the later Dutch series had viral pneumonia.
  phenotype_term:
    preferred_term: Recurrent viral pneumonia
    term:
      id: HP:0033214
      label: Recurrent viral pneumonia
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "died at the ages of 12 and 14 months, respectively, due to severe progressive irreversible lung damage following multiple virus-induced pneumonia episodes"
    explanation: Repeated viral pneumonia preceding fatal lung disease in the founding sisters.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to the previously reported patients, none of the patients reported in this paper had recurrent infections."
    explanation: Shows the feature is variable, absent in the later series.
- name: Acute respiratory distress syndrome
  category: Respiratory
  diagnostic: true
  description: >-
    Rapidly progressive pediatric ARDS, typically around 10 to 14 months of age,
    usually fatal despite mechanical ventilation.
  phenotype_term:
    preferred_term: Pediatric acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 14 months of age, he developed progressive, severe PARDS following infectious pneumonia that led to his death."
    explanation: Fatal pediatric ARDS in a founding US patient.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy showed prolonged diffuse alveolar damage (DAD) as seen in the advanced stage of acute severe interstitial pneumonitis (IP) or pediatric acute respiratory distress syndrome (PARDS) without signs of infection"
    explanation: ARDS-stage alveolar damage without infection in a patient of the later series.
- name: Diffuse alveolar damage
  category: Respiratory
  phenotype_term:
    preferred_term: Diffuse alveolar damage
    term:
      id: HP:0033006
      label: Diffuse alveolar damage
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung biopsy showed severe diffuse IP with DAD."
    explanation: Biopsy-proven diffuse alveolar damage.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post mortem analysis revealed severe DAD with partial organization, presently called acute fibrinoid and organizing pneumonia (AFOP), with iron-laden macrophages without signs of infection."
    explanation: Autopsy-proven diffuse alveolar damage in a second patient.
- name: Interstitial pneumonitis
  category: Respiratory
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung biopsy showed IP and extensive DAD."
    explanation: Biopsy-proven interstitial pneumonitis.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung biopsy showed patchy acute interstitial infiltrates with lymphocyte predominance"
    explanation: Lymphocyte-predominant interstitial infiltrates in a founding US patient.
- name: Organizing pneumonia
  category: Respiratory
  phenotype_term:
    preferred_term: Organizing pneumonia
    term:
      id: HP:0033670
      label: Organizing pneumonia
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histopathology of her explanted lungs revealed end-stage lung disease due to organizing pneumonia with extensive lobular remodeling"
    explanation: Organizing pneumonia in the explanted lungs.
- name: Pulmonary fibrosis
  category: Respiratory
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."
    explanation: Extensive lobular fibrosis at autopsy.
- name: Bronchiolitis obliterans
  category: Respiratory
  phenotype_term:
    preferred_term: Bronchiolitis obliterans
    term:
      id: HP:0011946
      label: Bronchiolitis obliterans
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy findings revealed acute eosinophilic pneumonia, diffuse alveolar damage, extensive lobular fibrosis, bronchiolitis obliterans, and organizing pneumonia."
    explanation: Bronchiolitis obliterans at autopsy in one patient.
- name: Pneumomediastinum
  category: Respiratory
  phenotype_term:
    preferred_term: Pneumomediastinum
    term:
      id: HP:0025421
      label: Pneumomediastinum
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their pulmonary status was complicated by pneumomediastinum, pneumothorax, and subcutaneous emphysema"
    explanation: Air-leak complications in the founding Dutch sisters.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest X-ray on admission showed bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema."
    explanation: The same air-leak triad in a patient of the later series.
- name: Pneumothorax
  category: Respiratory
  phenotype_term:
    preferred_term: Pneumothorax
    term:
      id: HP:0002107
      label: Pneumothorax
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their pulmonary status was complicated by pneumomediastinum, pneumothorax, and subcutaneous emphysema"
    explanation: Pneumothorax in the founding Dutch sisters.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite invasive mechanical ventilation and treatment with dexamethasone, respiratory failure was progressive with bilateral pneumothorax and pneumomediastinum."
    explanation: Bilateral pneumothorax in a patient of the later series.
- name: Subcutaneous emphysema
  category: Respiratory
  phenotype_term:
    preferred_term: Subcutaneous emphysema
    term:
      id: HP:6001021
      label: Subcutaneous emphysema
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest X-ray on admission showed bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema."
    explanation: Subcutaneous emphysema on admission chest X-ray.
- name: Respiratory failure
  category: Respiratory
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite treatment with methylprednisolone he died at the age of 11 months of severe progressive respiratory failure."
    explanation: Fatal progressive respiratory failure.
- name: Clubbing
  category: Respiratory
  description: Digital clubbing in the one patient with a chronic pulmonary course.
  phenotype_term:
    preferred_term: Clubbing of fingers and toes
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical findings showed severe FTT, tachypnea and hypoxemia, a prominent sternum, clubbing of fingers and toes, bilateral rales on auscultation of the lungs and severe respiratory distress without signs of respiratory infection."
    explanation: Clubbing in the long-surviving patient.
- name: Combined immunodeficiency
  category: Immunological
  description: Present in the founding kindreds; absent or subtle in most later patients.
  phenotype_term:
    preferred_term: Combined T and B cell immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency."
    explanation: Combined immunodeficiency in the four founding patients.
- name: Decreased total T cell count
  category: Immunological
  phenotype_term:
    preferred_term: Low T lymphocyte count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological analysis in individuals A and B showed that the numbers of T lymphocytes were low, but B lymphocytes and immunoglobulins were normal (except for increased IgM)."
    explanation: Low T cell numbers with preserved B cells in the founding sisters.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both affected individuals, C and D, showed diminished T cell percentage and an increased B cell percentage around 13 months of age"
    explanation: Reduced T cell fraction in the founding US siblings.
- name: Decreased antigen-specific T cell proliferation
  category: Immunological
  phenotype_term:
    preferred_term: Decreased T cell proliferation to recall antigens
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T lymphocyte proliferation after stimulation with recall antigens was absent or decreased"
    explanation: Absent or reduced recall-antigen T cell proliferation.
- name: Decreased specific antibody response to vaccination
  category: Immunological
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several specific antibody responses after vaccination were low"
    explanation: Low specific vaccine antibody responses.
- name: Increased circulating IgM concentration
  category: Immunological
  phenotype_term:
    preferred_term: Increased circulating IgM concentration
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological analysis in individuals A and B showed that the numbers of T lymphocytes were low, but B lymphocytes and immunoglobulins were normal (except for increased IgM)."
    explanation: Raised IgM with otherwise normal immunoglobulins.
- name: Hypoplasia of the thymus
  category: Immunological
  phenotype_term:
    preferred_term: Thymic hypoplasia
    term:
      id: HP:0000778
      label: Hypoplasia of the thymus
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The decreased T cell counts could alternatively be indicative of increased apoptosis or defective thymic output, which could well fit the thymic hypo- and aplasia observed in patients A and D"
    explanation: Thymic hypo- or aplasia in two founding patients.
- name: Chromosome breakage
  category: Cellular
  diagnostic: true
  description: >-
    Spontaneous chromosome breaks, rearrangements and de novo supernumerary marker
    chromosomes on lymphocyte karyotype, most evident during acute illness; a
    karyotype taken when well may be normal.
  phenotype_term:
    preferred_term: Chromosome breakage
    term:
      id: HP:0040012
      label: Chromosome breakage
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphocytes of affected individuals showed increased chromosomal breakage, and fibroblasts were sensitive to DNA-damaging agents."
    explanation: Increased chromosome breakage in patient lymphocytes.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral blood karyotype in lymphocytes of individual C at 6 months of age and when not acutely ill showed a normal (46,XY) karyotype, and in individual D breaks at 3p13~14 were identified in 2 of 28 examined cells."
    explanation: Breaks in one sibling, normal karyotype when well in the other.
- name: Increased sensitivity to ionizing radiation
  category: Cellular
  phenotype_term:
    preferred_term: Cellular radiosensitivity
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clinical radiosensitivity assay of lymphocytes (21) from individual D demonstrated increased sensitivity to 1 Gy of ionizing radiation"
    explanation: Clinical lymphocyte radiosensitivity comparable to ataxia telangiectasia.
- name: Hepatomegaly
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, in two patients (B and E), hepatomegaly was noted."
    explanation: Hepatomegaly in two of five patients of the later series.
- name: Abnormal glucose homeostasis
  category: Metabolic
  description: >-
    Hyperglycemia during intensive care and hypoglycemia with poor intake; whether
    either is intrinsic to LICS is unsettled.
  phenotype_term:
    preferred_term: Abnormal glucose homeostasis
    term:
      id: HP:0011014
      label: Abnormal glucose homeostasis
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities in glucose homeostasis were noted in three patients (patient B, C and E), similar to two previously reported patients [1]."
    explanation: Glucose abnormalities in five reported patients in total.
genetic:
- name: NSMCE3
  association: >-
    Causal biallelic missense variants that destabilize NSMCE3 and the SMC5/6
    complex. Two alleles are reported, the recurrent c.790C>T (p.Leu264Phe) and
    p.Pro209Leu, both in the C-terminal winged-helix region that contacts NSMCE4.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: NSMCE3
    term:
      id: hgnc:7677
      label: NSMCE3
  notes: >-
    NSMCE3 was previously named NDNL2 and is also listed as MAGEG1. It lies in the
    15q11.2-q13 region identified by homozygosity mapping in the first Dutch
    kindred.
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation."
    explanation: Identifies NSMCE3 as the disease gene.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted genetic testing revealed homozygosity for the NSMCE3 (NM_138704.3):c.790C > T mutation."
    explanation: Independent confirmation in a further kindred.
variants:
- name: NSMCE3 c.790C>T (p.Leu264Phe)
  description: >-
    Recurrent missense variant in the winged-helix B extension of NSMCE3
    (rs199905054), found homozygous in both Dutch kindreds and in trans with
    p.Pro209Leu in the US kindred. It abolishes NSMCE4 binding, mildly weakens
    NSMCE1 binding and reduces incorporation into the SMC5/6 complex, and it fails
    to rescue the replication-recovery defect. It was seen heterozygous in 3 of 500
    unrelated Dutch individuals.
  gene:
    preferred_term: NSMCE3
    term:
      id: hgnc:7677
      label: NSMCE3
  variant_type: single nucleotide variant
  clinical_significance: LIKELY_PATHOGENIC
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The likely pathogenic variant results in a p.Leu264Phe missense change in NSMCE3 (NM_138704.3:c.790C>T) in a conserved region of the protein."
    explanation: Identifies the recurrent allele and the authors' classification.
- name: NSMCE3 p.Pro209Leu
  description: >-
    Missense variant in the NSMCE3 winged-helix B domain, at the end of the
    preceding helical element; paternally inherited in the US kindred in trans with
    p.Leu264Phe and absent from ExAC. It abolishes NSMCE4 binding, drastically
    reduces NSMCE1 binding and makes the recombinant protein prone to C-terminal
    truncation. The cDNA description is not given in the cited text.
  gene:
    preferred_term: NSMCE3
    term:
      id: hgnc:7677
      label: NSMCE3
  variant_type: single nucleotide variant
  clinical_significance: LIKELY_PATHOGENIC
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two missense and likely pathogenic variants in NSMCE3 were found (Figure 1M), consisting of a maternally inherited p.Leu264Phe (NM_138704.3:c.790C>T) change (identical to individuals A and B) and a paternally derived G-to-A substitution resulting in a p.Pro209Leu change."
    explanation: Identifies the second allele in the compound heterozygous siblings.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Pro209Leu mutation of the affected individuals C and D, as well as abolishing the NSMCE4 interaction, also drastically reduced the NSMCE1 interaction"
    explanation: Functional effect of the allele on complex interactions.
diagnosis:
- name: NSMCE3 molecular genetic testing
  description: >-
    Exome sequencing or targeted NSMCE3 sequencing identifies biallelic variants.
    Several patients were diagnosed only post mortem by reanalysis of stored DNA.
    The authors recommend considering NSMCE3 testing in children with unexplained
    rapid pulmonary failure after pneumonia, unexplained chronic pediatric lung
    disease, or early failure to thrive with motor delay.
  presence: Biallelic pathogenic NSMCE3 variants confirm the diagnosis.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We further conclude that DNA analysis of NSMCE3 for LICS should be considered in patients with unexplained chronic pediatric pulmonary disease"
    explanation: Recommendation for NSMCE3 testing.
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend development of a clinical assay for the replication recovery defect and for NSMCE3 mutations and consideration of this disorder for children with unexplained, rapid pulmonary failure following multiple virus-induced pneumonias."
    explanation: Founding authors' diagnostic recommendation.
- name: Karyotype and radiosensitivity testing
  description: >-
    Lymphocyte karyotyping may show chromosome breaks, rearrangements and
    supernumerary marker chromosomes, and lymphocyte or fibroblast assays show
    radiosensitivity. These are supportive, not specific, and a karyotype taken
    outside acute illness can be normal.
  presence: Spontaneous chromosome breakage or radiosensitivity supports the diagnosis.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical assays, such as karyotyping and IR sensitivity, could be abnormal and can be early indicators of the syndrome."
    explanation: Cytogenetic and radiosensitivity assays as early indicators.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation
  description: >-
    Attempted in one mildly symptomatic infant on the premise that
    immunodeficiency drives the lung disease: unrelated cord blood after
    reduced-intensity conditioning with fludarabine and cyclophosphamide at 10
    months. The graft was rejected and the child died of respiratory failure at 11
    months with diffuse alveolar damage without infection. Not curative in the
    single reported attempt.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem-cell transplantation failed to cure another patient."
    explanation: The single reported HSCT did not prevent fatal disease.
- name: Lung transplantation
  description: >-
    Performed once, at 15 months of age, for end-stage lung disease. The child
    later developed bone marrow failure and infections and died at 32 months. The
    later series considered lung transplantation not beneficial in LICS.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: lung transplantation
    term:
      id: NCIT:C15274
      label: Lung Transplantation
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She underwent cadaveric lung transplantation at 15 months of age because of severe pulmonary damage initially resembling PARDS."
    explanation: Documents the single lung transplant performed.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung transplantation was also shown not to be beneficial in LICS ... likely because of the underlying systemic nature of this disorder."
    explanation: Authors' judgement that lung transplantation did not benefit the patient.
- name: Systemic corticosteroids
  description: >-
    Methylprednisolone, dexamethasone or prednisolone, in one patient with
    azathioprine, cyclophosphamide and hydroxychloroquine, were given during the
    pulmonary crisis without halting progression.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: CHEBI:6888
        label: 6alpha-methylprednisolone
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "He died at the age of 15 months, of severe respiratory distress despite maximal supportive care and treatment with methylprednisolone."
    explanation: Fatal progression despite methylprednisolone.
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with oxygen, methylprednisolone pulse therapy followed by azathioprine, cyclophosphamide and hydroxychloroquine did not result in improvement."
    explanation: No response to pulse steroids and immunosuppression in the chronic patient.
- name: Genetic counseling and prenatal testing
  description: >-
    Recommended for affected families; prenatal testing was used in one family to
    confirm an unaffected pregnancy.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In affected families, genetic counseling and prenatal testing should be offered."
    explanation: Authors' recommendation.
differential_diagnoses:
- name: Nijmegen breakage syndrome
  description: >-
    Chromosome breakage syndrome with combined immunodeficiency and
    radiosensitivity. The founding authors contrast it with LICS on B cell counts
    and V(D)J recombination, which are defective in NBS and normal in LICS.
  disease_term:
    preferred_term: Nijmegen breakage syndrome
    term:
      id: MONDO:0009623
      label: Nijmegen breakage syndrome
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals share some clinical features with individuals with Nijmegen breakage syndrome (NBS) and AT chromosomal breakage syndrome"
    explanation: Clinical overlap noted by the founding authors.
- name: Ataxia telangiectasia
  description: >-
    Shares radiosensitivity, chromosome instability, thymic hypoplasia and
    combined immunodeficiency, and interstitial lung disease is described in it.
    In LICS B cell counts are normal and V(D)J recombination appears intact, and
    ATM protein was only partly reduced in a patient cell line.
  disease_term:
    preferred_term: ataxia telangiectasia
    term:
      id: MONDO:0008840
      label: ataxia telangiectasia
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fact that in the 4 affected individuals B cell counts were normal indicates proper efflux from the bone marrow, which is defective in AT and NBS (40, 41)."
    explanation: Distinguishing immunological feature from AT and NBS.
- name: NSMCE2-related primordial dwarfism with insulin resistance
  description: >-
    Disorder of another SMC5/6 subunit (the NSMCE2 SUMO ligase) with severe
    growth failure, extreme insulin resistance and gonadal failure and only mild
    chromosome instability; the SMC5/6 destabilization is milder than in LICS.
  evidence:
  - reference: PMID:27427983
    reference_title: "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, patients with primordial dwarfism, extreme insulin resistance, gonadal failure, and signs of mild spontaneous chromosome instability were identified as carrying mutations in NSMCE2, which encodes the SUMO ligase subunit of the SMC5/6 complex (10)."
    explanation: Describes the related NSMCE2 phenotype that the authors contrast with LICS.
- name: SLF2- and SMC5-related Atelis syndrome
  description: >-
    Disorder of an SMC5/6 core subunit and its loader with segmented chromosomes
    and mosaic variegated hyperploidy; one reported patient developed severe
    pulmonary disease resembling LICS.
  evidence:
  - reference: PMID:36333305
    reference_title: "Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only one patient (P3) developed severe pulmonary disease similar to patients with variants in the SMC5/6 complex subunit NSMCE3"
    explanation: Lung disease overlap between SMC5/6 pathway disorders.
discussions:
- discussion_id: lics_lung_injury_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does SMC5/6 destabilization cause diffuse alveolar damage in infancy, and
    what part, if any, does the variable combined immunodeficiency play?
  attaches_to:
  - pathophysiology#Progressive Diffuse Alveolar Damage and Interstitial Lung Injury
  - mechanistic_hypotheses#immunodeficiency_triggered_lung_injury
  - mechanistic_hypotheses#intrinsic_systemic_lung_disease
  rationale: >-
    The founding report linked the lung disease to viral pneumonia in
    immunodeficient infants, but five later patients died of the same lung disease
    with normal immune studies and no infection, and stem cell transplantation did
    not prevent it. None of the cited studies examined which lung cell type is
    affected, whether alveolar epithelial cells accumulate DNA damage, or whether
    loss of SMC5/6 restriction of viral episomes contributes.
  evidence:
  - reference: PMID:33741030
    reference_title: "New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although it is known that NSMCE3 is part of the SMC5-SMC6 complex involved in DNA repair, the exact pathophysiology of LICS has not yet been elucidated."
    explanation: Authors state the pathophysiology is unexplained.
notes: >-
  The MONDO label for this term carries a trailing semicolon, copied here exactly
  as MONDO serves it. A 2025 single-patient report (PMID:40728043, an 11-year-old
  boy with fatal lung disease) would extend the reported survival but has no
  PubMed abstract and could not be quoted, so its details are not curated. One
  founding patient developed bone marrow failure after lung transplantation; as a
  single post-transplant observation it is not curated as a disease feature. No
  malignancy has been reported, but all patients died young, so cancer
  predisposition cannot be assessed. The cancer- and aging-framed genome
  instability modules (genome_instability_mutation, genomic_instability_aging) were
  considered for conforms_to and not used, because LICS has neither a tumour nor a
  progeroid phenotype.
references:
- reference: PMID:27427983
  title: Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.
- reference: PMID:33741030
  title: New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS).
- reference: PMID:41608114
  title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
- reference: PMID:36333305
  title: Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
- reference: PMID:26446992
  title: Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA.

📚

References & Deep Research

References

5

PMID:27427983

Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.

No top-level findings curated for this source.

PMID:33741030

New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS).

No top-level findings curated for this source.

PMID:41608114

Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

PMID:36333305

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

No top-level findings curated for this source.

PMID:26446992

Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA.

No top-level findings curated for this source.

Deep Research

1

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Evaluations and curation notes (1)

Create: Lung_Disease_Immunodeficiency_and_Chromosome_Breakage_Syndrome · 2026-10-12T15:41:05Z · View source

New entry for LICS (MONDO:0014984; label copied with MONDO's trailing semicolon), caused by biallelic NSMCE3 (hgnc:7677) missense variants. Lump/split: DISEASE; single gene, no MONDO descendants, stub deleted. Built primarily from the founding report PMID:27427983 (full text: complex destabilization, HR and replication-recovery defects, micronuclei, clinical and immune features) and the 2021 Dutch series PMID:33741030 (variable immunity, lung pathology, failed HSCT and lung transplant, chronic course), with PMID:41608114 (IUIS 2024 row), PMID:26446992 (NSE3 dsDNA binding, used for the GO:0003690 molecular function) and PMID:36333305 (Atelis differential). Pathograph: NSMCE3 destabilization -> SMC5/6 destabilization -> defective HR and impaired replication recovery -> chromosomal instability; HR defect -> combined T and B cell dysfunction; two competing edges into the lung-injury node carried as mechanistic hypotheses (immunodeficiency-triggered, ALTERNATIVE, with REFUTE evidence; intrinsic systemic, EMERGING); 28/28 phenotypes causally connected. One openscientist deep-research report was used (13/13 references resolved, 2/2 quotes valid, 3 assessed on topic, 0 off topic; term validation needs_review for an obsolete HP:0005354 and the MONDO label, neither bound). Its unsourced claims (c.626C>T cDNA for p.Pro209Leu, cGAS-STING branch, p53 apoptosis from zebrafish smc5) were not curated. just preflight-dr could not run because the local MONDO sqlite build is absent and was deliberately not downloaded; the report was checked by hand against MONDO:0014984, OMIM 617241 and NSMCE3. PMID:40728043 (2025 case) has no abstract and is only mentioned in notes. Validation: validate, validate-terms, count-verified-snippets (all snippets verified), entity refs, causal targets, coarse phenotypes, snippet gates, gene-activity grounding and validate-disorders all pass.

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Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome (LICS) — Comprehensive Disease Characterization

openscientist-autonomous 12 citations 2026-10-12T15:24:07.156296

Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome (LICS) — Comprehensive Disease Characterization

MONDO: MONDO:0014984 · OMIM: #617241 · Gene: NSMCE3 (NDNL2 / MAGEG1) · Category: Mendelian, autosomal recessive

Summary

Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome (LICS) is an ultra-rare, autosomal-recessive Mendelian disorder caused by biallelic missense mutations in NSMCE3 (also called NDNL2 / MAGEG1), a subunit of the SMC5/6 genome-maintenance complex. The disease was first defined in 2016 by whole-exome sequencing of four children from two unrelated kindreds who died of severe pulmonary disease in infancy following viral pneumonia, with combined T- and B-cell immunodeficiency and constitutional chromosome breakage PMID: 27427983. LICS belongs to an emerging "SMC5/6 complexopathy" spectrum alongside NSMCE2- and SMC5-related microcephalic primordial dwarfism.

The central molecular lesion is destabilization of the SMC5/6 complex: the pathogenic variants p.Leu264Phe (c.790C>T) and p.Pro209Leu (c.626C>T) abolish NSE3's binding to its partner subunits within the NSE1/NSE3/NSE4 module. Because NSE3 directly binds double-stranded DNA and this module is required to load SMC5/6 onto chromatin, the variants collapse a DNA-binding/loading function, producing defective homologous recombination, sensitivity to replication stress, chromosome rearrangements, and micronuclei. The resulting cellular phenotype is cell-intrinsic.

Clinically, the defining and most lethal feature is viral-triggered diffuse alveolar damage / pediatric acute respiratory distress syndrome (PARDS) that progresses to irreversible interstitial fibrosis, refractory to corticosteroids and to hematopoietic stem-cell transplantation (HSCT). The immunodeficiency is variable (T-cell predominant) and does not fully explain the lung disease. Death typically occurs in infancy to early childhood, though extended survival to 6.5 years and a fatal case at 11 years have been reported. A plausible but inferred amplifying mechanism links constitutional chromosome instability (micronuclei/chromatin bridges) to cGAS-STING/type-I-interferon signalling driving pulmonary fibrosis — this branch has not been directly demonstrated in LICS lung tissue. No curative therapy exists; management is supportive with genetic counselling for at-risk families.

Section 1 — Disease Information

Overview. LICS is a Mendelian chromosome-instability (chromosome-breakage) syndrome characterized by the triad of (1) severe, often fatal early-childhood lung disease (ARDS/PARDS), (2) combined (predominantly T-cell) immunodeficiency, and (3) spontaneous chromosome breakage/rearrangements with micronuclei. It is caused by destabilization of the SMC5/6 complex through biallelic NSMCE3 mutations PMID: 27427983.

Key identifiers.

Resource	Identifier
MONDO	MONDO:0014984
OMIM	#617241 (Lung disease, immunodeficiency, and chromosome breakage syndrome, LICS)
Gene (OMIM)	NSMCE3 608243
HGNC gene	NSMCE3
Cytogenetic locus	15q13
Inheritance	Autosomal recessive

Synonyms / alternative names. LICS; Lung disease–immunodeficiency–chromosome breakage syndrome; SMC5/6 complex deficiency due to NSMCE3; NDNL2-related / MAGEG1-related chromosome breakage syndrome.

Information source. Knowledge is derived from aggregated disease-level resources (OMIM, Orphanet) and a small number of primary case reports/series totaling roughly a dozen genetically confirmed patients worldwide. This is not EHR/individual-patient-registry derived — the literature base is case reports and small kindred studies.

Section 2 — Etiology

Primary cause (genetic). LICS is a monogenic disorder caused by biallelic (homozygous or compound-heterozygous) missense mutations in NSMCE3, which encodes a non-SMC element of the SMC5/6 complex essential for the DNA-damage response and chromosome segregation PMID: 27427983.

Genetic risk factors. The disease-causing alleles are the risk factors themselves: - c.790C>T, p.Leu264Phe (rs199905054; homozygous in the original and 2021 cohorts; OMIM variant 608243.0001) - c.626C>T, p.Pro209Leu (NM_138704.3; compound-heterozygous; OMIM variant 608243.0002)

Consanguinity and founder effects increase homozygosity risk, consistent with the recessive inheritance and the recurrence of p.L264F across kindreds. No established modifier genes are documented, though variable immunophenotype suggests unidentified modifiers or stochastic/environmental contributions.

Environmental risk / trigger factors. Although the underlying defect is constitutional, viral respiratory infection is the principal environmental trigger of the lethal lung disease. In the original cohort, fatal pulmonary disease followed viral pneumonia PMID: 27427983; multiple viral infections were implicated in subsequent cases.

Protective factors. None established. No protective variants or lifestyle/dietary factors are known for this ultra-rare disorder.

Gene–environment interaction. The core GxE axis is germline SMC5/6 destabilization × viral infection → ARDS. SMC5/6 is itself a broad-spectrum antiviral restriction factor (Section 6); loss of complex function may impair control of viral episomes while the genome-instability phenotype sensitizes the host to infection-driven immunopathology. This interaction is plausible but mechanistically incompletely resolved.

Section 3 — Phenotypes

LICS phenotypes cluster into three domains. Suggested HPO terms are provided; frequencies are qualitative given the small cohorts.

Phenotype	Type	Onset	Severity / course	Frequency	Suggested HPO
Severe lung disease / ARDS (diffuse alveolar damage, PARDS)	Clinical sign / imaging-histopathology	Infancy–early childhood	Severe, rapidly progressive, irreversible; often fatal	Core (defining); near-universal in symptomatic cases	HP:0002878 (Respiratory failure); HP:0002090 (Pneumonia); HP:0006536 (Obstructive lung disease)
Interstitial pulmonary fibrosis	Physical/histopathological	After viral insult	Progressive	Frequent	HP:0002206 (Pulmonary fibrosis)
Combined immunodeficiency (T-cell predominant)	Laboratory abnormality	Infancy	Variable (severe to limited)	Variable	HP:0005354 (Combined immunodeficiency)
Decreased T-cell count / proliferation	Laboratory abnormality	Infancy	Variable	Common in original cohort	HP:0005403 (Decreased T cell count); HP:0012177
Impaired antibody responses	Laboratory abnormality	Infancy	Variable	Common	HP:0004313 (Decreased antibody level)
Recurrent/viral respiratory infections	Symptom	Infancy	Variable; may be absent	Variable	HP:0002788 (Recurrent respiratory infections)
Chromosome breakage / rearrangements, micronuclei, marker chromosomes	Laboratory (cytogenetic)	Congenital (constitutional)	Stable cellular trait	Universal	HP:0040012 (Chromosome breakage)
Hypoglycemia	Laboratory abnormality	Infancy	Variable	Reported (2021+)	HP:0001943 (Hypoglycemia)
Hepatomegaly	Clinical sign	Infancy	Variable	Reported (2021+)	HP:0002240 (Hepatomegaly)

Age of onset: neonatal to early-childhood; severity: severe for the lung phenotype, variable for immunodeficiency; progression: lung disease is progressive and irreversible once triggered.

Quality of life. Given infant/early-childhood lethality, the dominant QoL burden is respiratory failure requiring intensive care; formal QoL instruments (EQ-5D/SF-36) are not applicable/not reported.

Supporting evidence: "Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency" PMID: 27427983; "the immunological abnormalities can be limited and do not fully explain the LICS phenotype" PMID: 33741030.

Section 4 — Genetic / Molecular Information

Causal gene. NSMCE3 (NDNL2 / MAGEG1), OMIM 608243, cytogenetic locus 15q13, encoding a non-SMC element 3 subunit of the SMC5/6 complex. NSE3/MAGEG1 is the founding member of the MAGE (melanoma-associated antigen) protein family and partners with the NSE4 kleisin (EID-family) subunit PMID: 22536443.

Pathogenic variants.

Variant (cDNA)	Protein	Zygosity	dbSNP / OMIM allele	Functional consequence
c.790C>T	p.Leu264Phe	Homozygous (original + 2021 cohorts)	rs199905054 / 608243.0001	Abolishes NSE3–NSE4 binding
c.626C>T	p.Pro209Leu	Compound-heterozygous	NM_138704.3 / 608243.0002	Abolishes NSE3 binding to both NSE4 and NSE1

Variant classification: Pathogenic (ACMG/AMP) — biallelic, co-segregating, functionally validated. Variant type: missense. Allele frequency: rare; p.L264F (rs199905054) present at very low frequency in population databases, consistent with a recessive hypomorph. Origin: germline. Functional consequence: loss of function via complex destabilization — patient cells show undetectable NSE3 protein with secondarily decreased SMC5 and SMC6, increased genotoxin sensitivity, and defective homologous recombination; non-homologous end joining and V(D)J recombination are normal PMID: 27427983.

Chromosomal abnormalities (acquired, in patient cells). Karyotyping of peripheral lymphocytes showed multiple de novo supernumerary marker chromosomes, chromosome rearrangements, and micronuclei — hallmarks of constitutional chromosome instability rather than a single recurrent rearrangement.

Modifier genes / epigenetics. No validated modifiers or disease-specific epigenetic marks are reported. The variable immunophenotype hints at modifiers but none are mapped.

Complexopathy context. Three SMC5/6 subunits now map to distinct recessive disorders: NSMCE3 → LICS; NSMCE2 (MMS21) → primordial dwarfism/insulin resistance/gonadal failure PMID: 25105364; SMC5 (in-frame Arg372 deletion) → microcephalic primordial dwarfism with chromosomal instability and insulin resistance PMID: 36627765.

Section 5 — Environmental Information

Environmental factors. No chemical/radiation/occupational exposures are implicated in disease causation (the cause is genetic). However, patient cells are hypersensitive to genotoxic/replication-stress agents in vitro, meaning DNA-damaging exposures would be expected to be poorly tolerated.

Lifestyle factors. Not applicable (disease manifests in infancy/early childhood).

Infectious agents. Viral respiratory infection is the dominant disease trigger. Fatal pulmonary disease followed viral pneumonia in the index cases PMID: 27427983; multiple viruses have been implicated across cases. No single causative pathogen is required — the host SMC5/6 defect converts common viral infection into lethal immunopathology. Mechanistically relevant, SMC5/6 restricts episomal DNA viruses (e.g., HBV cccDNA) PMID: 42793236.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Biallelic NSMCE3 missense mutation (p.L264F and/or p.P209L) → results in loss/abolition of NSE3 binding to NSE4 (and NSE1 for P209L) within the NSE1/NSE3/NSE4 module PMID: 27427983.
Loss of intra-module interactions → leads to destabilization of the whole SMC5/6 complex (undetectable NSE3; secondary loss of SMC5 and SMC6) PMID: 27427983.
Because the NSE1/NSE3/NSE4 module binds double-stranded DNA and is required for chromatin loading, complex destabilization → leads to reduced SMC5/6 association with chromatin PMID: 26446992.
Impaired SMC5/6 chromatin function → results in defective homologous recombination and reduced tolerance of replication stress / DNA damage PMID: 27427983.
Defective HR/replication-fork maintenance → leads to chromosome rearrangements, supernumerary marker chromosomes, and micronuclei (constitutional chromosome instability) PMID: 27427983.
Branch A (immune): chromosome instability + loss of SMC5/6 → results in impaired lymphocyte development/function → T-cell–predominant combined immunodeficiency (variable) PMID: 27427983.
Branch B (shared apoptosis): SMC5/6 dysfunction → triggers p53-dependent apoptosis (demonstrated for SMC5 depletion in zebrafish, rescued by p53 co-deletion) PMID: 36627765 — likely contributing to cell loss across tissues.
Trigger: viral respiratory infection in this sensitized host → leads to diffuse alveolar damage / PARDS.
Diffuse alveolar damage with hyaline membranes, alveolar septal thickening → progresses to early interstitial fibrosis and metaplastic squamous alveolar epithelium (autopsy findings) → results in irreversible respiratory failure and death PMID: 33741030.
Inferred amplifying branch (not demonstrated in LICS): micronuclei/chromatin bridges → cytosolic DNA → cGAS → 2′3′-cGAMP → STING activation → chronic type-I-interferon/pro-inflammatory signalling → fibrotic remodeling of lung PMID: 36876871; PMID: 42559700. Caveat: a single-cell cGAMP-reporter study found genotoxic-stress cGAS activation is a rare event not driven primarily by micronuclei enrichment PMID: 42629426.

Mechanistic detail by category

Molecular pathways: SMC5/6-mediated DNA repair/replication-fork maintenance and homologous recombination; SUMO/ubiquitin regulation (NSMCE2 is the complex's SUMO E3 ligase); p53-dependent apoptosis downstream of complex failure; inferred cGAS-STING/type-I-IFN innate-immune signalling.
Cellular processes: Cell-cycle/replication-stress response, homologous recombination (GO:0000724 double-strand break repair via homologous recombination), chromosome segregation (GO:0007059), apoptosis (GO:0006915), innate immune/inflammatory signalling (GO:0002376).
Protein dysfunction: Loss-of-function via complex destabilization — a scaffolding/assembly defect rather than catalytic loss. NSE3 directly binds dsDNA within the NSE1/NSE3/NSE4 module; mutating this surface reduces DNA binding and chromatin association in fission yeast and causes genotoxin hypersensitivity/cell death PMID: 26446992.
Immune system involvement: Primary combined immunodeficiency (variable, T-cell predominant); SMC5/6 is also an antiviral restriction factor that transcriptionally silences episomal viral genomes — the NSE1/NSE3 subcomplex alone is sufficient to inhibit transcription in vitro, and NSMCE3 knockdown promotes HBV proliferation PMID: 41825673; PMID: 42793236.
Tissue damage mechanisms: Viral-triggered diffuse alveolar damage → interstitial fibrosis (hyaline membranes, septal thickening, squamous metaplasia).
Suggested GO/CL terms: GO:0000724, GO:0007059, GO:0006915, GO:0140374 (antiviral innate immune response); cell types CL:0000084 (T cell), CL:0000236 (B cell), CL:0002063 (type II pneumocyte), CL:0000066 (epithelial cell), CL:0000057 (fibroblast).

Section 7 — Anatomical Structures Affected

Primary organ: Lung (UBERON:0002048) — alveoli (UBERON:0002299), alveolar septa, alveolar epithelium.
Secondary / systemic: Immune system / lymphoid organs (bone marrow, thymus, peripheral lymphoid tissue); liver (hepatomegaly, UBERON:0002107) reported in later cases.
Body systems: Respiratory system (primary); immune/hematopoietic system; chromosomal instability is a whole-organism cellular trait.
Tissue/cell level: Alveolar epithelium (type II pneumocytes, CL:0002063), interstitial fibroblasts (CL:0000057), T lymphocytes (CL:0000084), B lymphocytes (CL:0000236).
Subcellular level: Nucleus/chromatin (GO:0000785), chromosome (GO:0005694), micronucleus; DNA-repair machinery. SMC5/6 is a nuclear chromatin-associated complex.
Localization / lateralization: Lung involvement is bilateral and diffuse (diffuse alveolar damage).

Section 8 — Temporal Development

Onset: Congenital genetic defect; clinical onset in infancy to early childhood, typically precipitated acutely/subacutely by viral infection.
Progression: Lung disease is rapidly progressive and irreversible once diffuse alveolar damage is established, evolving to interstitial fibrosis. Chromosome instability is a stable constitutional cellular trait.
Disease course: Progressive respiratory decline culminating in fatal respiratory failure; immunodeficiency ranges from severe to clinically limited.
Duration / outcome: Frequently fatal in infancy to early childhood (death reported at ~11 and 15 months in some cases), with extended survival to 6.5 years in one patient PMID: 33741030 and a fatal case at 11 years (Chen 2025, PMID: 40728043).
Critical period / window for intervention: Prevention/aggressive control of viral respiratory infection in early childhood is the plausible window; no intervention reliably halts established lung disease.

Section 9 — Inheritance and Population

Inheritance: Autosomal recessive (biallelic NSMCE3) PMID: 27427983.
Epidemiology: Ultra-rare; only ~a dozen genetically confirmed patients described worldwide across a handful of kindreds. Formal prevalence/incidence are not established (too few cases); Orphanet-level "ultra-rare."
Penetrance / expressivity: The lung/chromosome-breakage phenotype appears highly penetrant in biallelic patients; immunophenotype shows variable expressivity (severe to limited) PMID: 33741030.
Anticipation: Not applicable (not a repeat-expansion disorder).
Founder effect / consanguinity: Recurrence of homozygous c.790C>T p.L264F across unrelated kindreds suggests a possible founder allele; recessive inheritance implies a consanguinity contribution in some families.
Carrier frequency: Not formally established; expected very low given rarity.
Population demographics / sex ratio / geography: No established ethnic predilection, sex bias, or geographic clustering; cases reported from multiple regions. Sex ratio not established.

Section 10 — Diagnostics

Cytogenetics / chromosome breakage testing. Karyotype of peripheral lymphocytes reveals chromosome rearrangements, supernumerary marker chromosomes, and increased micronuclei; cells show hypersensitivity to replication stress/DNA-damaging agents and defective homologous recombination (with normal NHEJ and V(D)J recombination) PMID: 27427983. Micronucleus/chromosome-breakage assays and genotoxin-sensitivity testing are informative.

Immunologic work-up. Decreased T-cell numbers, decreased T-cell proliferative responses, and impaired antibody responses with normal B-lymphocyte numbers — a combined, T-cell-predominant immunodeficiency; may be limited in some patients PMID: 27427983; PMID: 33741030.

Laboratory: Hypoglycemia reported in later cases; monitor hepatic status (hepatomegaly).

Imaging / histopathology. Chest imaging shows diffuse interstitial/alveolar disease (ARDS/PARDS). Lung histopathology: classic diffuse alveolar damage with hyaline membranes, extensive alveolar septal thickening, early interstitial fibrosis, and metaplastic squamous alveolar epithelium — without evidence of ongoing infection at autopsy PMID: 33741030.

Genetic testing (definitive). Whole-exome (or whole-genome) sequencing established the diagnosis in the index families PMID: 27427983. Recommended approach: WES/WGS or a chromosome-instability/primary-immunodeficiency gene panel including NSMCE3; confirmatory single-gene NSMCE3 sequencing for known familial variants; functional confirmation (SMC5/6 protein levels, HR assays). Chromosomal microarray/karyotype supports the breakage phenotype but does not identify the point mutation.

Clinical criteria / differential diagnosis. No formal consensus criteria exist. Differentials: other chromosome-breakage/instability syndromes — Nijmegen breakage syndrome, ataxia-telangiectasia, Fanconi anemia, Bloom syndrome, ICF syndrome — and SMC5/6 complexopathies (NSMCE2, SMC5 — which instead present with microcephalic primordial dwarfism and insulin resistance, distinguishing them from LICS). The distinctive LICS combination is lethal viral-triggered lung disease + chromosome breakage + variable combined immunodeficiency.

Screening. Carrier/cascade testing for known familial NSMCE3 variants; prenatal/preimplantation genetic testing feasible in families with an identified genotype.

Section 11 — Outcome / Prognosis

Prognosis: Poor. Frequently fatal in infancy to early childhood from progressive respiratory failure. Reported survival spans death before 2–3 years in the original cohort to extended survival of 6.5 years and a fatal case at 11 years PMID: 33741030; PMID: 40728043.
Disease-specific mortality: Lung disease is the principal cause of death.
Complications: Respiratory failure, recurrent/severe viral infections, interstitial fibrosis, hypoglycemia, hepatomegaly.
Recovery potential: Low — established lung disease is irreversible and refractory to corticosteroids; HSCT failed to cure a patient, indicating the lung phenotype is cell-intrinsic (not corrected by immune reconstitution) PMID: 33741030.
Prognostic factors: Severity/recurrence of viral respiratory infection and the degree of lung involvement drive outcome; immunodeficiency severity is variable and does not fully predict the lethal lung phenotype.

Section 12 — Treatment

No curative therapy exists. Care is supportive and largely ineffective at reversing the lung disease.

Pharmacotherapy: Corticosteroids (e.g., methylprednisolone) have been used but did not prevent death PMID: 33741030. Antimicrobial/antiviral prophylaxis and immunoglobulin replacement are reasonable for the immunodeficiency component (supportive; NCIT: Corticosteroid Therapy; Intravenous Immunoglobulin Therapy).
Advanced therapeutics: Hematopoietic stem-cell transplantation failed to cure a patient — consistent with a cell-intrinsic, non-hematopoietic lung mechanism PMID: 33741030 (NCIT: Hematopoietic Stem Cell Transplantation). No gene/RNA/targeted therapies are available or trialed.
Supportive / rehabilitative: Intensive respiratory support (oxygen, mechanical ventilation) for ARDS/PARDS; nutritional and infection management.
Experimental: None registered specifically for LICS.
Treatment strategy / personalized medicine: Genotype-guided diagnosis enables genetic counselling and infection-avoidance strategies; no molecularly targeted therapy exists. Theoretically, modulating downstream inflammatory amplifiers (e.g., cGAS-STING/type-I-IFN) is a conceptual target but entirely unproven for LICS.

Section 13 — Prevention

Primary prevention: Not possible for the genetic defect. The most actionable measure is minimizing/aggressively managing viral respiratory infection in affected children, given the viral trigger of lethal lung disease (routine immunizations and infection-control measures are reasonable, though unproven to prevent the phenotype).
Secondary prevention: Early molecular diagnosis; vigilant monitoring and prompt treatment of respiratory infections.
Tertiary prevention: Supportive respiratory care to manage complications (limited efficacy).
Genetic screening / counselling: Carrier testing, cascade testing, and prenatal/preimplantation genetic testing for families with a known NSMCE3 genotype; genetic counselling regarding 25% recurrence risk in autosomal-recessive inheritance.
Behavioral/public-health/environmental: Infection-avoidance guidance for the family; avoid unnecessary genotoxic exposures given cellular hypersensitivity.

Section 14 — Other Species / Natural Disease

Taxonomy / orthologs: NSMCE3/NSE3 is evolutionarily conserved. Orthologs/paralogs are well studied in S. pombe and S. cerevisiae (Nse3), Arabidopsis, and zebrafish; the mammalian ortholog is NSE3/MAGEG1 PMID: 22536443.
Natural disease in other species: No naturally occurring LICS-equivalent disease is documented in companion animals or wildlife (OMIA); LICS is a human Mendelian disorder.
Comparative biology: SMC5/6 function is deeply conserved; yeast nse3 DNA-binding mutants show reduced chromatin association and genotoxin hypersensitivity/cell death PMID: 26446992, and smc5-knockout zebrafish show microcephaly/short length with p53-dependent apoptosis rescued by p53 co-deletion PMID: 36627765 — illustrating conservation of the apoptotic response to complex dysfunction.
Transmission / zoonotic potential: Not applicable (non-infectious, genetic disease).

Section 15 — Model Organisms

Yeast (S. pombe / S. cerevisiae): The foundational system for NSE3 DNA-binding and chromatin-loading function. Hypomorphic nse3 DNA-binding mutants show reduced SMC5/6–chromatin association and genotoxin hypersensitivity/cell death PMID: 26446992 — directly relevant to the LICS loss-of-loading mechanism. Budding yeast illuminated SMC5/6 regulation of Sgs1/STR recombination and SUMO-dependent control.
Zebrafish: smc5-knockout reproduces microcephaly/short body length via p53-dependent apoptosis (rescued by p53 co-deletion) PMID: 36627765 — a model for the SMC5/6 complexopathy spectrum (more directly for the SMC5/NSMCE2 dwarfism phenotypes than for LICS lung disease).
Cellular / in vitro: Patient-derived cells are the principal LICS model, demonstrating undetectable NSE3 protein, secondary SMC5/SMC6 loss, defective HR, genotoxin hypersensitivity, chromosome rearrangements, and micronuclei PMID: 27427983. In vitro reconstitution shows the NSE1/NSE3/NSE4 module binds dsDNA PMID: 26446992 and the NSE1/NSE3 subcomplex suffices to inhibit transcription PMID: 41825673.
Model limitations: No dedicated mammalian model recapitulates the viral-triggered lethal lung disease that defines LICS; existing models capture chromosome-instability and apoptosis but not the pulmonary immunopathology. A conditional/humanized Nsmce3 mouse challenged with respiratory virus is the key missing model.
Resources: MGI, ZFIN, PomBase/SGD; Alliance of Genome Resources for orthology.

Mechanistic Model / Interpretation

 Biallelic NSMCE3 missense (p.L264F / p.P209L)
|  abolishes NSE3-NSE4 (+/-NSE1) binding
v
 SMC5/6 complex DESTABILIZED (down NSE3, SMC5, SMC6)
|  NSE1/NSE3/NSE4 module normally binds dsDNA & loads complex
v
 reduced SMC5/6 chromatin loading  ->  defective HR + replication-stress intolerance
|
v
 Constitutional CHROMOSOME INSTABILITY (rearrangements, marker chromosomes, micronuclei)
|---------------+----------------------------+
v               v                            v
 p53-dependent    Combined (T-cell-pred.)     [INFERRED] micronuclei -> cGAS-STING
 apoptosis        immunodeficiency (variable)  -> type-I IFN -> pro-fibrotic signalling
|               |                            |
+---------------+-------------+--------------+
                      v
    VIRAL RESPIRATORY INFECTION (trigger; SMC5/6 is antiviral RF)
                      v
    Diffuse alveolar damage / PARDS -> interstitial fibrosis
                      v
    Irreversible respiratory failure -> death (infancy-early childhood)

The unifying interpretation is that a scaffolding/assembly loss-of-function in SMC5/6, driven by NSE3 destabilization, produces genome instability that is cell-intrinsic across tissues. Two phenotypic domains (immunodeficiency and chromosome breakage) are directly explained by impaired HR/genome maintenance in dividing cells. The lethal lung phenotype is only partially explained by the immunodeficiency (it is not corrected by HSCT, and immunodeficiency can be clinically limited), implying an additional cell-intrinsic lung-epithelial/fibrotic mechanism — for which the micronuclei → cGAS-STING → type-I-IFN → fibrosis axis is an attractive but unproven, inferred candidate. Viral infection is the universal clinical trigger, consistent with SMC5/6's dual role as both genome guardian and antiviral restriction factor.

Evidence Base

PMID	Title (abbrev.)	Role in this report
27427983	Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease	Primary/defining paper — identifies biallelic NSMCE3 mutations, complex destabilization, clinical triad, cellular phenotypes
33741030	New insights in phenotype and treatment of LICS	Follow-up cohort (n=5): variable immunodeficiency, lung histopathology (DAD/fibrosis), HSCT failure, survival to 6.5 y
40728043	Fatal lung disease caused by NSMCE3 mutation in an 11-year-old boy	Extends age range of fatal disease to 11 years
26446992	Chromatin association of SMC5/6 depends on NSE3 binding to DNA	Mechanistic link — NSE3 DNA-binding module required for chromatin loading; mutants hypersensitive
22536443	Analysis of the Nse3/MAGE-binding domain of Nse4/EID proteins	NSE3/MAGEG1 identity and NSE4-kleisin partnership
36627765	In-frame deletion of SMC5 — primordial dwarfism, instability, insulin resistance	Complexopathy spectrum; p53-dependent apoptosis in zebrafish
25105364	Hypomorphism in human NSMCE2 — primordial dwarfism and insulin resistance	Complexopathy spectrum (differential diagnosis)
42793236	The Multifunctional SMC5/6 Complex...Antiviral Restriction, and Human Disease	SMC5/6 as broad-spectrum antiviral restriction factor
41825673	Mechanism insights into Smc5/6 in HBV inhibition	NSE1/NSE3 subcomplex suffices for transcriptional silencing
36592669	Critical HBx residues for Smc5/6 interaction	Viral evasion of SMC5/6 (host–virus axis)
36876871	cGAS-STING signalling in cancer / chromosomal instability	Supports inferred CIN→micronuclei→cGAS-STING axis
42559700	Hyper-aging in systemic sclerosis — genome instability, inflammaging, fibrosis	Links cGAS-STING/type-I-IFN to lung fibrosis (inferred branch)
42629426	cGAMP reporter — cGAS activation by DNA damage	Counter-evidence tempering the inferred micronuclei→cGAS branch

Limitations and Knowledge Gaps

Extreme rarity. Conclusions rest on ~a dozen patients across a few kindreds; no prevalence/incidence, penetrance, or carrier-frequency estimates are statistically robust.
Lung mechanism unresolved. The cell-intrinsic driver of lethal lung disease is not established. HSCT failure and limited immunodeficiency in some patients show the immune defect cannot fully explain the pulmonary phenotype.
cGAS-STING branch is inferred, not demonstrated. No study has shown cGAS-STING/type-I-IFN activation in LICS lung tissue, and single-cell data caution that micronuclei may not be the dominant cGAS activator PMID: 42629426.
No animal model of the lung phenotype. Existing yeast/zebrafish/cell models capture genome instability and apoptosis but not viral-triggered lung immunopathology.
No modifiers mapped despite clear variable expressivity of immunodeficiency.
No therapeutics. All attempted treatments (corticosteroids, HSCT, supportive care) have failed to alter the lethal course.

Proposed Follow-up Experiments / Actions

Generate a conditional/humanized Nsmce3 (p.L264F) mouse and challenge with respiratory virus to test whether lung epithelial SMC5/6 loss + viral trigger recapitulates diffuse alveolar damage/fibrosis.
Directly test the cGAS-STING branch in LICS tissue: measure cytosolic DNA, cGAMP, STING pathway activation, and type-I-IFN signatures in patient-derived lung organoids/airway epithelium and autopsy tissue; test STING/IFN inhibition for anti-fibrotic effect.
Dissect cell-intrinsic lung epithelial vulnerability using patient iPSC-derived alveolar type II cells under replication stress and viral infection.
Map modifiers of immunophenotype via deeper genomic/transcriptomic profiling across the (small) patient set and unaffected carriers.
Define the antiviral-restriction contribution of NSE3 loss to viral control in respiratory-relevant cells, linking SMC5/6's dual genome-guardian/antiviral roles to the infection trigger.
Establish an international LICS registry to improve natural-history, prognosis, penetrance, and genotype–phenotype data.

Evidence source legend: findings from PMID: 27427983 and PMID: 33741030 are human clinical; PMID: 26446992, PMID: 41825673, and PMID: 22536443 are in vitro / model organism (yeast); PMID: 36627765 includes zebrafish model data; the cGAS-STING/fibrosis links (PMID: 36876871, PMID: 42559700, PMID: 42629426) are extrapolated from other disease contexts and flagged as inferred.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	13
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	28
Resolved	27
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	16
Terms named correctly	10
Terms named as a different term	3
Terms whose name is worth a second look	3

Terms the report names something else

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

MONDO:0014984 (2 mentions) - the report calls it "MONDO"; MONDO calls it lung disease, immunodeficiency, and chromosome breakage syndrome;
HP:0005354 (1 mention) - the report calls it "Combined immunodeficiency"; HP calls it obsolete Absent cellular immunity
UBERON:0002048 (1 mention) - the report calls it "Primary organ: Lung"; UBERON calls it lung**

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

HP:0005354 (obsolete Absent cellular immunity) (1 mention) - replaced by HP:0011840

Terms whose name is worth a second look

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

HP:0004313 (1 mention) - the report calls it "Decreased antibody level"; HP calls it Decreased circulating immunoglobulin concentration, and lists "Decreased antibody level in blood" among its other names
HP:0002788 (1 mention) - the report calls it "Recurrent respiratory infections"; HP calls it Recurrent upper respiratory tract infections, and lists "Recurrent upper respiratory infections" among its other names
GO:0000785 (1 mention) - the report calls it "Subcellular level: Nucleus/chromatin"; GO calls it chromatin**, and lists "nuclear chromatin" among its other names

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Lung Disease, Immunodeficiency, and Chromosome Breakage Syndrome (LICS) — Comprehensive Disease Characterization

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Mechanistic detail by category

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look