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Classifications

Harrison's Chapter

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Definitions

2

Advanced Sleep-Wake Phase Disorder Diagnostic Criteria (ICSD-3-aligned)

Consensus clinical criteria for advanced sleep-wake phase disorder. The defining requirements are (a) a stable advance of the major sleep episode relative to the desired or required sleep and wake times, (b) symptoms - evening sleepiness and/or early-morning awakening - present for at least three months, (c) improvement in sleep quality and duration when the individual is allowed to follow their own preferred early schedule, (d) objective corroboration by sleep diary plus actigraphy for at least seven and preferably fourteen days including both work and free days, and (e) exclusion of another sleep, medical, neurological, psychiatric, medication-related, or environmental explanation.

DIAGNOSTIC_CRITERIA

Core clinical criteria

Criteria that must be jointly satisfied to diagnose ASWPD rather than a non-disordered advanced chronotype.

Core clinical characteristics

Advance of the major sleep episode relative to desired sleep-wake time
Evening sleepiness
Early-morning awakening with inability to return to sleep

Exclusion criteria

Another sleep, medical, neurological, psychiatric, medication-related, or environmental explanation for the sleep timing

Additional requirements

Sleep onset and wake times occur at least 2 hours earlier than the societal norm
Symptoms present for at least three months
Sleep quality and duration improve when following the self-selected early schedule
Sleep diary plus actigraphy for at least 7 (preferably 14) days, including work and free days

Show evidence (4 references)

PMID:34493186 SUPPORT Other

"The main clinical manifestations are insomnia and excessive daytime sleepiness that often lead to clinically meaningful distress or cause mental, physical, social, occupational, educational, or other functional impairment."

Supports the requirement that symptoms produce clinically meaningful distress or functional impairment, which is what distinguishes the disorder from a well-tolerated advanced chronotype.

PMID:39864932 SUPPORT Other

"Advanced sleep-wake phase disorder (ASWPD) is characterized by a consistent and distressing anticipation of sleep-wake timing"

Supports the core criterion of a consistent (stable) and distressing advance of sleep-wake timing.

PMID:34493186 SUPPORT Other

"2) symptoms are present for at least 3 months; 3) when patients are allowed to sleep in accordance with their internal biological clock, sleep quality and duration are improved with a consistent but advanced timing of the major sleep episode; 4) sleep logs and, whenever possible, actigraphy..."

Verbatim statement of ICSD criteria 2-5, directly sourcing the numeric thresholds used in this criteria set (3 months; 7-14 days of sleep logs plus actigraphy) as well as the improvement-on-preferred-schedule requirement and the exclusion criterion.

+ 1 more reference

Show evidence (1 reference)

PMID:34493186 SUPPORT Other

"Sleep diaries, actigraphy, and determination of day and night phase markers (dim light melatonin onset and core body temperature minimum) have all become routine diagnostic methods for CRSWDs."

Establishes the routine objective diagnostic measures required by the criteria set.

Notes: The distress/impairment requirement is what separates ASWPD (a disorder) from an extreme but well-tolerated advanced chronotype. Many people with a markedly advanced phase never meet criteria because they arrange their lives around it. PROVENANCE: every numeric threshold in this criteria set is now sourced to a verbatim quotation. PMID:34493186 restates the five ICSD criteria in full ("The diagnosis of ASWPD requires that the following five main criteria are met") and separately gives the >=2 hour advance threshold. The definition is named "ICSD-3-aligned" because the criteria are quoted from a review restating them rather than from the ICSD-3 manual itself, which is not PubMed-indexed and therefore not citable under the project's snippet rules.

Dim Light Melatonin Onset (DLMO) Phase Assessment

The reference measurement protocol for objectively locating circadian phase. Serial salivary or plasma melatonin samples are collected under dim-light conditions over several hours before habitual bedtime, and DLMO is the clock time at which melatonin rises above a defined assay threshold. In ASPS, DLMO occurs abnormally early. Core body temperature minimum is an equivalent phase marker. DLMO is what converts a patient report of early sleep into a demonstrated circadian phase advance, and it is what allows light therapy to be timed on the correct side of the phase-response curve - which is why it is a treatment-enabling measurement, not merely a confirmatory one.

OTHER

Show evidence (3 references)

clinicaltrials:NCT04690504 SUPPORT Human Clinical

"circadian phase estimates from the biomarker panels will be compared with those derived from plasma or saliva melatonin (the current "gold-standard" circadian phase marker)"

Establishes plasma/saliva melatonin phase as the current gold-standard circadian phase marker - the reason no separate validation status is asserted for DLMO itself.

clinicaltrials:NCT04690504 SUPPORT Human Clinical

"Current methods for assessing circadian timing require sampling over hours (or even up to a day) while the patient is in controlled conditions."

Documents the serial-sampling-under-controlled-conditions burden that defines the DLMO protocol and motivates ongoing biomarker development.

PMID:10470086 SUPPORT Human Clinical

"Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau."

Demonstrates that the melatonin and temperature phase markers are advanced in ASPS, which is what DLMO assessment detects.

Notes: Typed as OTHER rather than PHENOTYPE_ALGORITHM: this is a laboratory phase-assessment protocol, not a computable EHR/OMOP case-finding query, which is what PHENOTYPE_ALGORITHM denotes in this schema. No `validation_status` is asserted, because DLMO IS the reference standard for circadian phase - it is the comparator against which candidate biomarkers are validated, so it cannot coherently be marked VALIDATED_AGAINST_GOLD_STANDARD against itself. A specific numeric salivary-melatonin threshold is deliberately not stated here; thresholds are assay- and laboratory-dependent and no cached source states one verbatim. See also the parallel `diagnosis` entry, which records DLMO as a diagnostic test; this entry records the measurement definition.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Familial ASPS segregates as an autosomal dominant trait with high penetrance. Penetrance across genes and families beyond the original kindreds is not well quantified and may be modified by age and light environment.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:10470086 SUPPORT Human Clinical

"The trait segregates as an autosomal dominant with high penetrance."

Directly establishes autosomal dominant inheritance with high penetrance.

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Subtypes

2

Familial Advanced Sleep Phase Syndrome (FASPS/FASP)

Autosomal dominant inheritance

The inherited form, segregating as an autosomal dominant trait with high penetrance. Typically emerges before age 30 and is present in a first-degree relative. Caused by variants in core circadian clock genes (PER2, CSNK1D, CRY2, PER3, TIMELESS) that shorten the intrinsic circadian period or alter photic entrainment. This is the form to which the MONDO concept and its familial advanced sleep-phase syndrome synonyms most directly correspond, and it is the mechanistic centrepiece of this entry.

Show evidence (2 references)

PMID:10470086 SUPPORT Human Clinical

"Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance."

The original description of FASPS establishes the autosomal dominant, highly penetrant familial subtype with a short intrinsic period.

PMID:39864932 SUPPORT Other

"Advanced sleep phase (ASP) is seldom brought to medical attention because many individuals easily adapt to their early chronotype, especially if it emerges before the age of 30 and is present in a first-degree relative. In this case, the disorder is considered familial (FASP)"

Defines the familial subtype by early onset plus a first-degree relative, and notes its characteristic under-ascertainment.

Sporadic and Age-Related Advanced Sleep Phase

The non-familial form, in which advanced sleep timing arises without an identified Mendelian variant. Advanced sleep timing becomes progressively more common with age, and age-related circadian change is compounded by neurodegenerative disease affecting the suprachiasmatic nucleus and by reduced sensitivity and responsiveness to light. Early morning awakening occurs in roughly 4% of older individuals, and distressing advanced sleep-wake timing (ASWPD) affects approximately 1% of middle-aged adults.

Show evidence (2 references)

PMID:39864932 SUPPORT Other

"Early morning awakening is, instead, more common among older individuals, occurring in almost 4% of cases, without considering associated comorbidities. Advanced sleep-wake phase disorder (ASWPD) is characterized by a consistent and distressing anticipation of sleep-wake timing, affecting almost..."

Distinguishes the age-related/sporadic form and quantifies early morning awakening in older adults and ASWPD in middle age.

PMID:39864932 SUPPORT Other

"Age-related alterations in circadian rhythms are exacerbated and compounded by neurodegenerative disorders, impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and light responsiveness in those affected."

Identifies the SCN and photic-responsiveness substrate of the age-related subtype, distinguishing it mechanistically from the Mendelian form.

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Discussions and Knowledge Gaps

3

Is PER3 a genuine advanced-sleep-phase gene, or is the reported P415A/H417R association confounded by the co-reported seasonal mood trait?

KNOWLEDGE GAP OPEN asps_per3_validity

Attached to

pathophysiology#PER3 Destabilization

The PER3 association rests on a single kindred carrying a two-variant haplotype, and the reported human phenotype bundles familial advanced sleep phase with elevated Beck Depression Inventory and seasonality scores rather than isolated phase advance. The functional data (destabilized PER3, failure to stabilize PER1/PER2) are real but do not by themselves establish that phase advance, rather than the mood/seasonality trait, is the PER3-attributable phenotype. This entry therefore types PER3 as DISPUTED rather than CAUSATIVE. No ClinGen gene-disease validity classification exists for any ASPS gene.

Proposed experiments

Independent kindred replication for PER3

asps_exp_per3_replication

Identify additional unrelated kindreds segregating PER3 variants with advanced sleep phase, ideally separating the two variants of the P415A/H417R haplotype to determine which (if either) drives the circadian phenotype.

Phase-versus-mood phenotype separation in PER3 carriers

asps_exp_per3_phase_vs_mood

Phenotype PER3 variant carriers with DLMO and actigraphy alongside structured mood and seasonality assessment, to determine whether phase advance occurs independently of the mood trait.

Show evidence (1 reference)

PMID:26903630 SUPPORT Human Clinical

"We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores."

Documents the confounded phenotype - advanced sleep phase reported together with a mood/seasonality trait - that motivates this gap.

Does correctly timed morning melatonin actually produce clinically meaningful phase delay in ASWPD without unacceptable daytime sedation?

KNOWLEDGE GAP OPEN asps_melatonin_evidence_gap

Attached to

pathophysiology#Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity

Morning melatonin is mechanistically indicated for ASWPD by the melatonin phase-response curve, and review literature names advanced sleep phase among the disorders in which timed melatonin is useful. But the AASM guideline could make no recommendation for melatonin in ASWPD, the review literature states outright that clinical safety and effectiveness data are lacking, and the sedative effect of morning dosing may undermine the very schedule the treatment is meant to establish. The evidence for this treatment therefore carries a deliberate mixture of SUPPORT, NO_EVIDENCE, and REFUTE items in this entry - an honest reflection of an unresolved question rather than an internal inconsistency.

Proposed experiments

Randomized trial of DLMO-timed morning melatonin in ASWPD

asps_exp_melatonin_rct

Randomized placebo-controlled trial of morning melatonin timed against individually measured DLMO, in DLMO-confirmed ASWPD, with DLMO shift and actigraphic sleep timing as primary endpoints and next-day sleepiness plus schedule adherence as co-primary safety endpoints, since sedation is the predicted failure mode.

Show evidence (1 reference)

PMID:34493186 SUPPORT Other

"However, there is a lack of clinical data and information regarding the safety and effectiveness of melatonin"

States the evidence gap directly.

What is the specific TIMELESS variant causing familial advanced sleep phase, and what is the penetrance of each ASPS gene?

KNOWLEDGE GAP OPEN asps_variant_and_penetrance_reporting

Attached to

pathophysiology#TIMELESS Nuclear Exclusion

The cached TIMELESS abstract establishes that a human TIMELESS mutation causes FASP and characterizes its molecular consequences, but names no specific variant, so this entry deliberately declines to assert one rather than importing an unverifiable variant name from the deep-research report. More broadly, penetrance is quantified for none of the five ASPS genes beyond the original PER2 kindreds being described as highly penetrant, and penetrance may be age- and light-environment-dependent. This limits both variant interpretation and genetic counselling.

Proposed experiments

Source the TIMELESS variant to a citable record

asps_exp_timeless_variant_sourcing

Extract the specific TIMELESS variant with HGVS nomenclature against a stated transcript from the primary full text and ClinVar, so it can be asserted with a verifiable citation.

Age-stratified penetrance estimation across ASPS genes

asps_exp_penetrance

Aggregate reported kindreds per gene to estimate age-specific penetrance, recording light environment and habitual schedule as covariates given that both are expected to modify expression.

Show evidence (1 reference)

PMID:31138685 SUPPORT Human Clinical

"Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP)."

Establishes the gene-disease claim while naming no variant - the gap this discussion records.

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Pathophysiology

13

Age-Related Suprachiasmatic Nucleus Decline

The trigger of the SPORADIC / AGE-RELATED arm, mechanistically distinct from the Mendelian arm. With advancing age - and compounded by neurodegenerative disease - the suprachiasmatic nucleus itself is affected, reducing the robustness and amplitude of central pacemaker output. This is a degenerative/structural route to an unstable, easily-advanced clock rather than a change in the kinetics of the molecular oscillator, and it explains why advanced sleep timing becomes progressively more common with age. It is the arm that accounts for the substantially higher population-level prevalence figures (approximately 1% of middle-aged adults, and early morning awakening in about 4% of older individuals) relative to the rare Mendelian kindreds.

Suprachiasmatic nucleus pacemaker neuron CL:4072019

Regulation of circadian rhythm GO:0042752 ↓ DECREASED

Suprachiasmatic nucleus UBERON:0002034

Downstream

Reduced Photic Sensitivity and Light Responsiveness SCN decline is accompanied by reduced sensitivity and responsiveness to the entraining light signal.

Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity Reduced pacemaker amplitude and robustness permit a drift to an earlier phase, independently of any change in intrinsic period.

Show evidence (2 references)

PMID:39864932 SUPPORT Other

"Age-related alterations in circadian rhythms are exacerbated and compounded by neurodegenerative disorders, impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and light responsiveness in those affected."

Directly identifies the SCN as the anatomical substrate of the age-related arm, and names neurodegenerative disease as an exacerbating factor.

PMID:34493186 SUPPORT Human Clinical

"A large survey of a middle-aged and elderly population (40~64 years old) showed that the prevalence of ASWPD was approximately 1%, and increased with age; however, no gender differences were found"

Establishes the age-dependence of ASWPD prevalence, the epidemiological signature of this non-Mendelian arm.

Reduced Photic Sensitivity and Light Responsiveness

The mediating step of the sporadic/age-related arm. Ageing reduces both the sensitivity of the circadian system to light and its responsiveness to it - through the SCN and its input pathway - so the daily zeitgeber signal that normally holds the clock at the correct phase is weakened. A weakened entraining signal is less able to oppose a drift toward earlier timing, and it also blunts the response to the evening light used therapeutically, which is part of why light therapy is harder to deliver effectively in exactly the older population in which this arm predominates. A behavioral positive-feedback loop compounds this: early awakening leads to premature morning light exposure, which falls on the phase-advance limb of the phase-response curve and advances the clock further.

Intrinsically photosensitive retinal ganglion cell CL:0020014

Entrainment of circadian clock by photoperiod GO:0043153 ↓ DECREASED

Retina UBERON:0000966

Downstream

Altered Photic Entrainment of the Circadian Pacemaker A weakened photic input degrades entrainment, converging on the same node through which the Mendelian TIMELESS and CRY2 lesions act.

Show evidence (2 references)

PMID:39864932 SUPPORT Other

"impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and light responsiveness in those affected"

Names reduced sensitivity to light and reduced light responsiveness explicitly as components of the age-related circadian alteration.

PMID:34493186 SUPPORT Other

"If an individual receives less light in the afternoon or evening, or is prematurely exposed to morning light following early awakening, the circadian rhythm can be advanced, leading to an increased risk of an early sleep phase"

Evidences the behavioral positive-feedback loop - early awakening brings forward light exposure, which advances the clock further.

Autosomal Dominant Core Clock Gene Variant

A germline, autosomal dominant variant in a component of the core circadian transcription-translation feedback loop (TTFL) or its regulatory kinase. In the canonical loop, CLOCK-BMAL1 activates transcription of PER and CRY; PER/CRY protein complexes accumulate, are phosphorylated, enter the nucleus, and repress CLOCK-BMAL1. The rate constants of this loop - phosphorylation, degradation, and nuclear entry - set the intrinsic period (tau). FASPS variants perturb exactly these rate constants. Reported genes are PER2, CSNK1D, CRY2, PER3, and TIMELESS.

Suprachiasmatic nucleus pacemaker neuron CL:4072019

PER2 hgnc:8846 CSNK1D hgnc:2452 CRY2 hgnc:2385 PER3 hgnc:8847 TIMELESS hgnc:11813

Circadian rhythm GO:0007623 Circadian regulation of gene expression GO:0032922

Suprachiasmatic nucleus UBERON:0002034

Downstream

PER2 CK1-Site Hypophosphorylation PER2 S662G removes the CK1delta/epsilon phosphoacceptor serine.

CK1delta Reduced Kinase Activity CSNK1D T44A reduces the enzymatic activity of the kinase itself.

CRY2 Destabilization by FBXL3 CRY2 A260T increases FBXL3 affinity and CRY2 turnover.

TIMELESS Nuclear Exclusion A TIMELESS mutation prevents nuclear accumulation of TIM.

PER3 Destabilization PER3 P415A/H417R destabilizes PER3 protein.

Show evidence (2 references)

PMID:39864932 SUPPORT Other

"Autosomal dominant mutations in circadian clock genes like PER2, CK1, PER3, CRY2, TIMELESS, and DEC2 have been linked to FASP, some with pleiotropic effects influencing other health aspects like migraine and depression."

Review enumerates the autosomal dominant core clock genes implicated in familial advanced sleep phase.

PMID:31400754 SUPPORT Other

"A portion of the variation in the population is controlled by genetics as shown by the single-gene mutations that confer extreme early or late chronotypes."

Establishes that single-gene clock mutations are sufficient to produce extreme early chronotype, the genetic premise of this node.

PER2 CK1-Site Hypophosphorylation

The original FASPS lesion, PER2 p.Ser662Gly (S662G), substitutes glycine for a serine that lies within the casein kinase I epsilon/delta binding region of hPER2 and is itself a CK1 phosphoacceptor. Loss of this phosphoacceptor causes PER2 to be hypophosphorylated by CK1 in vitro. Because CK1-dependent phosphorylation of PER2 governs both PER2 transcriptional feedback and PER2 protein turnover, the substitution retunes the feedback loop and alters the circadian period. This is the substrate side of the PER2/CK1delta lesion pair.

PER2 hgnc:8846

Protein phosphorylation GO:0006468 ↓ DECREASED Regulation of circadian rhythm GO:0042752

Downstream

Altered PER/CRY Negative Feedback on CLOCK-BMAL1 Hypophosphorylated PER2 alters the timing and strength of PER/CRY repression of CLOCK-BMAL1.

Show evidence (3 references)

PMID:11232563 SUPPORT Human Clinical

"Affected individuals have a serine to glycine mutation within the casein kinase Iepsilon (CKIepsilon) binding region of hPER2"

Human genetic finding - establishes the serine-to-glycine substitution in the CK1epsilon binding region of hPER2 in affected individuals.

PMID:11232563 SUPPORT In Vitro

"which causes hypophosphorylation by CKIepsilon in vitro"

Biochemical finding, split from the human genetic item above because the authors state the hypophosphorylation result is in vitro. This is the evidence for the phosphorylation defect itself.

PMID:17218255 SUPPORT Model Organism

"We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation."

Mouse modelling of S662G recapitulates the human phenotype and shows the phosphosite controls PER2 transcription and, at other sites, degradation.

CK1delta Reduced Kinase Activity

CSNK1D p.Thr44Ala (T44A) mutates the kinase rather than the substrate: casein kinase I delta acts on the same PER2 phosphorylation axis that is disrupted by PER2 S662G. (The published evidence for the linkage is dosage epistasis - altering CKIdelta dosage modulates the S662 phenotype - rather than a direct demonstration that CK1delta phosphorylates residue 662 itself.) The T44A mutant kinase has decreased enzymatic activity in vitro. This is the enzyme side of the same molecular lesion, and it phenocopies PER2 S662G - a strikingly clean piece of mechanistic evidence, because the substrate lesion and the kinase lesion converge on a single biochemical event (CK1-dependent PER2 phosphorylation) and produce the same human phenotype. Transgenic mice bearing CKIdelta-T44A have a shortened circadian period mimicking human FASPS, and CKIdelta gene dosage modulates the PER2 S662G phenotype in vivo, formally demonstrating that the two lesions act on the same axis.

CSNK1D hgnc:2452

Protein phosphorylation GO:0006468 ↓ DECREASED

Downstream

PER2 CK1-Site Hypophosphorylation Reduced CK1delta enzymatic activity produces the same end state as loss of the PER2 phosphoacceptor serine - hypophosphorylated PER2. This is the kinase-side-to-substrate-side convergence that makes the PER2/CSNK1D pair unusually strong mechanistic evidence.

Show evidence (3 references)

PMID:15800623 SUPPORT Human Clinical

"We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS."

Human genetic finding - establishes CSNK1D T44A as a FASPS-causing variant.

PMID:15800623 SUPPORT In Vitro

"This mutant kinase has decreased enzymatic activity in vitro."

Biochemical finding, split from the human genetic item above because the authors state the reduced kinase activity is an in vitro result. This is the evidence for the enzymatic defect itself.

PMID:15800623 SUPPORT Model Organism

"In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS."

Mouse model of CKIdelta T44A shows the period shortening that underlies the human phase advance. Note the accompanying Drosophila transgenic showed a lengthened period, so the direction of effect is species-dependent and the mammalian model is the relevant one.

CRY2 Destabilization by FBXL3

CRY2 p.Ala260Thr (A260T) lies in the phosphate loop of the FAD-binding domain of CRY2. The substitution changes CRY2 conformation so as to increase its accessibility and affinity for FBXL3, an E3 ubiquitin ligase, thereby promoting CRY2 ubiquitination and degradation. Accelerated turnover of this negative-limb repressor shortens the circadian period.

CRY2 hgnc:2385

Protein ubiquitination GO:0016567 ↑ INCREASED Protein destabilization GO:0031648 ↑ INCREASED

Downstream

Altered PER/CRY Negative Feedback on CLOCK-BMAL1 Accelerated CRY2 degradation weakens and shortens repression.

Altered Photic Entrainment of the Circadian Pacemaker The CRY2 variant additionally reduces the phase-shifting response to an early-night light pulse, so it acts on the entrainment arm as well as on period - the two routes are not mutually exclusive.

Show evidence (2 references)

PMID:27529127 SUPPORT Human Clinical

"We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene that co-segregates with FASP in one family. The mutation leads to replacement of an alanine residue at position 260 with a threonine (A260T)."

Establishes CRY2 A260T co-segregating with familial advanced sleep phase.

PMID:27529127 SUPPORT In Vitro

"The mutation alters the conformation of CRY2, increasing its accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus promoting its degradation."

Directly establishes the FBXL3-mediated degradation mechanism for the A260T variant.

TIMELESS Nuclear Exclusion

A mutation in human TIMELESS (hTIM) prevents TIM from accumulating in the nucleus and alters its affinity for CRY2, destabilizing the PER/CRY complex and weakening repression of CLOCK-BMAL1. Notably, this variant produces advanced sleep phase primarily by altering photic entrainment rather than by shortening the organismal period: CRISPR mutant mice show advanced sleep phase with altered photic entrainment but a normal circadian period, even though period shortening is seen in mutant fibroblasts. What distinguishes TIMELESS from the other FASPS lesions is specifically the NORMAL organismal period - entrainment involvement as such is not unique to it, since the CRY2 A260T variant also shows a reduced phase-shift to early-night light while additionally shortening period.

TIMELESS hgnc:11813

Protein import into nucleus GO:0006606 ↓ DECREASED Entrainment of circadian clock by photoperiod GO:0043153

Downstream

Altered PER/CRY Negative Feedback on CLOCK-BMAL1 Cytoplasmic TIM destabilizes the PER/CRY repressor complex.

Altered Photic Entrainment of the Circadian Pacemaker The dominant route for this variant - altered phase responsiveness to light rather than a shortened intrinsic period.

Show evidence (3 references)

PMID:31138685 SUPPORT Human Clinical

"Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP)."

Establishes TIMELESS as a FASP gene in humans.

PMID:31138685 SUPPORT In Vitro

"We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs)."

Establishes nuclear exclusion, altered CRY2 affinity, and PER/CRY destabilization as the molecular consequence.

PMID:31138685 PARTIAL Model Organism

"Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period."

Qualifies the mechanism - for TIMELESS the organismal phenotype arises via altered photic entrainment, not via a shortened organismal period. This is why the entry models a separate entrainment branch.

PER3 Destabilization

Two rare PER3 variants (p.Pro415Ala and p.His417Arg, PER3-P415A/H417R) were identified in individuals with familial advanced sleep phase who also had higher Beck Depression Inventory and seasonality scores. The variants destabilize PER3 and fail to stabilize PER1/PER2 proteins. The evidence base here is weaker than for PER2 or CSNK1D - a single kindred with a two-variant haplotype, and the human phenotype is co-reported with a mood trait rather than isolated phase advance - so this node is curated as a contributory rather than an established mechanism.

PER3 hgnc:8847

Protein destabilization GO:0031648 ↑ INCREASED

Downstream

Altered PER/CRY Negative Feedback on CLOCK-BMAL1 PER3 destabilization removes stabilizing support for PER1/PER2, the direct repressor-limb components.

Show evidence (2 references)

PMID:26903630 SUPPORT Human Clinical

"We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores."

Establishes the PER3 variants in familial advanced sleep phase, with the important caveat that the phenotype was co-reported with a mood trait.

PMID:26903630 SUPPORT In Vitro

"Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing."

Provides the destabilization mechanism and its link to PER1/PER2, the intermediate in the causal edge.

Altered PER/CRY Negative Feedback on CLOCK-BMAL1

All of the established FASPS lesions converge here. The TTFL keeps time because PER/CRY repressor complexes accumulate, are post-translationally delayed, enter the nucleus, repress CLOCK-BMAL1, and are then degraded, permitting the next cycle. Reducing the delay - by hypophosphorylating PER2 (PER2 S662G, CSNK1D T44A), by accelerating CRY2 degradation (CRY2 A260T), or by destabilizing the PER/CRY complex (TIMELESS, PER3) - makes each iteration of the loop complete faster. This is the shared molecular convergence point of the disorder.

Circadian regulation of gene expression GO:0032922 PER/CRY transcriptional repression of CLOCK-BMAL1 GO:0045892

Downstream

Shortened Intrinsic Circadian Period A faster feedback loop yields a shorter free-running period.

Show evidence (1 reference)

PMID:11232563 SUPPORT Human Clinical

"Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period."

Establishes that a clock-component variant acts by altering the circadian period, the output of this convergence node.

Altered Photic Entrainment of the Circadian Pacemaker

Light reaching intrinsically photosensitive retinal ganglion cells is conveyed by the retinohypothalamic tract to the suprachiasmatic nucleus and is the dominant zeitgeber that entrains the clock to the 24-hour day. The direction of the resulting shift depends on when in the circadian cycle the light falls (the phase-response curve): light in the late night/early morning advances the clock, light in the evening delays it. A clock lesion can therefore advance phase either by shortening period or by biasing this entrainment response, and the TIMELESS variant acts predominantly through the latter. This node is also the substrate on which treatment acts, and the reason mistimed light worsens the disorder.

Intrinsically photosensitive retinal ganglion cell CL:0020014

Entrainment of circadian clock by photoperiod GO:0043153

Retina UBERON:0000966 Suprachiasmatic nucleus UBERON:0002034

Downstream

Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity Biased entrainment settles the clock at an abnormally early phase.

Show evidence (4 references)

PMID:31138685 SUPPORT Model Organism

"We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP."

Establishes altered light entrainment as a distinct causal route to familial advanced sleep phase.

PMID:21243069 SUPPORT Other

"Light is the strongest entraining agent of circadian rhythms and timed exposure to bright light is often used in the treatment of circadian rhythm sleep disorders."

Establishes light as the dominant entraining agent and the basis of timed-light therapy acting on this node.

PMID:34493186 SUPPORT Other

"Studies have also shown that morning light can advance, while evening light or light before bedtime can delay the phase of the circadian rhythm"

Directly evidences the DIRECTIONALITY of the phase-response curve that this node asserts, and which underpins both the pathophysiology (morning light reinforces an advance) and the treatment (evening light corrects it). This is the sentence that makes the ASWPD-versus-DSWPD mirror-image logic evidentiable rather than merely asserted.

+ 1 more reference

Shortened Intrinsic Circadian Period

The hallmark physiological abnormality of Mendelian FASPS - a free-running circadian period (tau) measurably shorter than the normal ~24.2 hours. A clock that runs fast must be reset backwards each day by the zeitgeber; the steady-state consequence of entraining a short-period oscillator to a 24-hour day is that it settles at an abnormally early phase angle. This is the direct mechanistic explanation for why a period abnormality produces a phase abnormality, and it is the reason FASPS individuals are phase-advanced rather than simply free-running.

Circadian rhythm GO:0007623 Regulation of circadian rhythm GO:0042752

Suprachiasmatic nucleus UBERON:0002034

Downstream

Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity A short-period oscillator entrained to a 24-hour day stabilizes at an advanced phase angle of entrainment.

Show evidence (3 references)

PMID:10470086 SUPPORT Human Clinical

"Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau."

Directly links the short intrinsic period (tau) to the profound phase advance in humans.

PMID:10470086 SUPPORT Model Organism

"Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively."

States the general period-to-phase principle established in rodents that predicted, and explains, the human phenotype.

PMID:27529127 SUPPORT Model Organism

"In mice, the CRY2 mutation causes a shortened circadian period and reduced phase-shift to early-night light pulse associated with phase-advanced behavioral rhythms in the light-dark cycle."

Independent genetic confirmation that period shortening produces phase-advanced behavioral rhythms.

Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity

The integrated organism-level output - the entire circadian ensemble, pineal melatonin secretion, core body temperature nadir, and the circadian drive for sleep, is displaced several hours earlier than normal. In the original FASPS kindreds this amounted to roughly a 4-hour advance of the sleep, temperature, and melatonin rhythms. Crucially, the oscillation itself is intact and of normal amplitude; only its phase is shifted. This is why sleep architecture and duration remain normal, and why the disorder is one of timing rather than of sleep quality.

Circadian sleep/wake cycle GO:0042745 Circadian behavior GO:0048512

Pineal body UBERON:0001905

Downstream

Early Chronotype

Advanced Melatonin Secretion Phase The pineal melatonin rhythm is one component of the displaced circadian ensemble, and the one used clinically as the phase marker (DLMO).

Early Evening Sleep Onset

Early Morning Awakening

Evening Sleepiness

Preserved Sleep Quality and Duration on a Self-Selected Schedule Because only phase, not oscillator integrity, is disturbed, sleep is normal when permitted to occur at the advanced biological time.

Circadian Misalignment with Conventional Social Schedule

Show evidence (1 reference)

PMID:11232563 SUPPORT Human Clinical

"Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms."

Quantifies the coordinated multi-marker phase advance that defines this node.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Endocrine 1

Advanced Melatonin Secretion Phase Abnormal pineal melatonin secretion HP:0012689

HP:0012689 is defined as "An anomaly in the amount or timing of melatonin secretion by the pineal gland", so the timing sense is within its scope; the more specific claim (advance rather than delay) is carried by preferred_term and description, as HPO has no direction-specific child.

Show evidence (2 references)

PMID:11232563 SUPPORT Human Clinical

"affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms"

Quantifies the advance of the melatonin rhythm specifically, which is what DLMO measurement detects.

PMID:10470086 SUPPORT Human Clinical

"Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau."

Independently documents the profound phase advance of the melatonin rhythm in the original kindreds.

Nervous System 2

Evening Sleepiness Drowsiness HP:0002329

Temporal: DIURNAL

`frequency:` is deliberately omitted. The cited source reports no per-symptom frequency data for evening sleepiness, and no quantitative frequency band could be justified from the available abstracts. Per the project frequency-evidence guidelines, omission is preferred to a fabricated band.

Show evidence (1 reference)

PMID:31384946 PARTIAL Human Clinical

"This can optimize treatment for evening sleepiness and early morning awakening"

Identifies evening sleepiness (paired with early morning awakening) as the treatable symptom complex of extreme advanced chronotypes. Marked PARTIAL because this is a conclusions-section statement about treatment targets in a prevalence study, not a direct observation of the phenotype or its frequency.

Sleep Restriction and Functional Impairment Sleep disturbance HP:0002360

Temporal: CHRONIC

Show evidence (1 reference)

PMID:34493186 SUPPORT Other

"The main clinical manifestations are insomnia and excessive daytime sleepiness that often lead to clinically meaningful distress or cause mental, physical, social, occupational, educational, or other functional impairment."

Documents the functional-impairment domains that result from circadian sleep-wake disorders.

Other 4

Early Chronotype VERY_FREQUENT Early chronotype HP:0031873

Course: STABLE

Show evidence (2 references)

PMID:11232563 SUPPORT Human Clinical

"affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms"

Describes the extreme morning chronotype that defines affected individuals.

PMID:10470086 SUPPORT Human Clinical

"Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare."

Distinguishes the disabling extreme chronotype of ASPS from the common mild morning preference.

Early Evening Sleep Onset VERY_FREQUENT Early chronotype HP:0031873

Temporal: CHRONIC

NEEDS TERM (NTR candidate). This phenotype shares HP:0031873 with `Early Chronotype`, but the two are distinct claims: HP:0031873 is defined as "A tendency towards rising very early in the morning and going to bed early in the evening" - a stable trait disposition - whereas this row asserts the specific clock-time observation of involuntary sleep onset in the early evening. "Advanced sleep onset" is an EXACT synonym of HP:0031873, so it is the correct available binding, and the alternative (the grandparent HP:0006979 Sleep-wake cycle disturbance) is direction-neutral and would fit delayed sleep phase equally well. A distinct HPO child term for advanced sleep onset would resolve the reuse.

Show evidence (2 references)

PMID:15800623 SUPPORT Human Clinical

"Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening."

Directly documents early sleep times as a defining clinical feature.

PMID:10470086 SUPPORT Human Clinical

"This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset"

Defines very early sleep onset as a core characteristic of the disorder.

Early Morning Awakening VERY_FREQUENT Terminal insomnia HP:0031356

Temporal: CHRONIC

Show evidence (2 references)

PMID:15800623 SUPPORT Human Clinical

"Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening."

Directly documents early-morning awakening as a defining clinical feature.

PMID:34493186 SUPPORT Other

"CRSWDs are easily mistaken for insomnia or early waking up, resulting in inappropriate treatment."

Supports that the early awakening of a circadian disorder is commonly misattributed to an insomnia disorder, leading to inappropriate therapy.

Preserved Sleep Quality and Duration on a Self-Selected Schedule

Deliberately curated WITHOUT a phenotype_term. This assertion is the ABSENCE of a sleep-quality abnormality, so binding any HPO abnormality term (e.g. HP:0006979 Sleep-wake cycle disturbance) would make the entry assert the negation of its own claim and would be read by downstream consumers as a positive abnormality. HPO has no "normal sleep architecture" term; a normality/negation construct or a new term request would be needed. The same discriminating information is carried in the Insomnia Disorder and Major Depressive Disorder differential_diagnoses and in the ICSD-3 criteria set.

Show evidence (4 references)

PMID:34493186 SUPPORT Other

"Unlike other sleep maintenance disorders, early morning awakenings occur after a normal period of undisturbed sleep, that is, the sleep cycle is normal for the age."

Directly evidences the discriminating feature - the early awakening follows a NORMAL, undisturbed sleep period, explicitly contrasted with other sleep-maintenance disorders. This is the sentence that separates ASWPD from insomnia disorder.

PMID:34493186 SUPPORT Other

"If the patient is allowed to sleep according to his wishes, the PSG results show a normal sleep structure."

Objective polysomnographic confirmation that sleep architecture is normal when the patient sleeps on their own advanced schedule - the strongest form of this claim.

PMID:34493186 SUPPORT Other

"In addition, unlike excessive sleepiness due to other reasons, the daytime work or learning ability of people with this disorder is not affected by sleepiness."

Distinguishes ASWPD from primary hypersomnias - daytime function is preserved, consistent with normal sleep quantity and quality.

+ 1 more reference

🧬

Genetic Associations

5

PER2

Gene: PER2 hgnc:8846 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11232563 SUPPORT Human Clinical

"Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (hPer2), a human homolog of the period gene in Drosophila, maps to the same locus."

Establishes PER2 as the FASPS gene by positional mapping to 2qter.

CSNK1D

Gene: CSNK1D hgnc:2452 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15800623 SUPPORT Human Clinical

"We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS."

Establishes CSNK1D T44A as causative for FASPS.

CRY2

Gene: CRY2 hgnc:2385 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27529127 SUPPORT Human Clinical

"We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene that co-segregates with FASP in one family."

Establishes CRY2 A260T co-segregation with FASP. Note the evidence base is a single family.

TIMELESS

Gene: TIMELESS hgnc:11813 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:31138685 SUPPORT Human Clinical

"Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP)."

Establishes TIMELESS as a FASP gene.

PER3

Gene: PER3 hgnc:8847 relationship_type: DISPUTED

Show evidence (1 reference)

PMID:26903630 PARTIAL Human Clinical

"We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores."

Supports a PER3 contribution but only partially, because the reported phenotype bundles advanced sleep phase with a mood/seasonality trait and derives from a single kindred.

💊

Medical Actions

3

Timed Evening Bright Light Therapy

Action: bright white light therapy Ontology label: Bright White Light Therapy NCIT:C174524

The principal evidence-based treatment. Bright light delivered in the evening falls on the phase-delay portion of the human phase-response curve and pushes the advanced clock later. Phototherapy for ASWPD is usually given between 19:00 and 21:00, and the recommended dose to achieve a phase delay is at least 5,000 lux for 2 hours at night. The AASM 2015 guideline gives light therapy positive endorsement, at a second-tier degree of confidence, for adults with ASWPD, and the AASM guideline is summarized in the review literature as recommending night bright light therapy for ASWPD specifically. Tolerability is the main practical limitation: multiple studies report that elderly patients exposed to bright light at night could not tolerate it, resulting in poor compliance, and one comparison found better compliance (and symptom improvement) with dim rather than enhanced-intensity evening light. Side effects are otherwise minimal (eye fatigue, nausea, restlessness, headache) and usually self-limiting. DIRECTION IS CRITICAL. The same intervention mistimed does harm - morning bright light falls on the phase-advance portion of the curve and would further advance an already-advanced clock, worsening the disorder. Correct timing therefore depends on knowing circadian phase (DLMO or core body temperature minimum), not merely clock time. Tolerance of prolonged evening light can be poor in older adults, the group in whom ASPS is most common.

Mechanism Target:

MODULATES Altered Photic Entrainment of the Circadian Pacemaker — Evening light exploits the delay portion of the phase-response curve to shift the entrained phase later, counteracting the advance.

Show evidence (6 references)

PMID:26414986 SUPPORT Human Clinical

"light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia)"

AASM guideline gives light therapy (with or without behavioral interventions) positive second-tier endorsement specifically for adults with ASWPD.

PMID:21243069 SUPPORT Other

"Light is the strongest entraining agent of circadian rhythms and timed exposure to bright light is often used in the treatment of circadian rhythm sleep disorders."

Supports timed bright light as the principal entraining intervention for circadian rhythm sleep disorders.

PMID:34493186 SUPPORT Other

"Phototherapy is usually performed between 19:00~21:00 hours, which can improve sleep efficiency and delay the circadian rhythm"

Provides the specific EVENING timing window (19:00-21:00) and confirms the intended direction of effect is a circadian DELAY - the direction that corrects an advanced phase.

+ 3 more references

Strategically Timed Melatonin

Action: Pharmacotherapy NCIT:C15986

Agent: melatonin CHEBI:16796

Exogenous melatonin shifts circadian phase according to a phase-response curve that is approximately the inverse of the light PRC - melatonin taken in the morning delays the clock, whereas melatonin taken in the evening advances it. For ASPS the theoretically correct direction is therefore MORNING melatonin to produce a phase delay, the exact opposite of the evening dosing used in delayed sleep-wake phase disorder. Evening melatonin would advance the clock further and is expected to worsen ASPS. This treatment is included because review-level literature reports timed melatonin as useful across circadian rhythm sleep disorders including advanced sleep phase, but it must be flagged that the AASM 2015 guideline did NOT endorse melatonin for ASWPD - its melatonin endorsement was restricted to DSWPD, blind adults with N24SWD, and children/adolescents with ISWRD. Morning dosing also risks residual daytime sleepiness. Melatonin for ASPS should therefore be regarded as mechanistically rational but not guideline-supported.

Mechanism Target:

MODULATES Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity — Morning-timed exogenous melatonin acts on the melatonin phase-response curve to delay the advanced circadian phase.

Show evidence (5 references)

PMID:21243069 SUPPORT Other

"In addition, timed administration of melatonin, either alone or in combination with light therapy has been shown to be useful in the treatment of the following circadian rhythm sleep disorders: delayed sleep phase, advanced sleep phase, free-running, irregular sleep wake, jet lag and shift work."

Review-level support for timed melatonin, explicitly naming advanced sleep phase among the circadian disorders in which it is useful.

PMID:34493186 SUPPORT Other

"According to the melatonin PRC, to delay the circadian rhythm phase of ASWPD, melatonin should be given in the early morning."

Directly evidences the DIRECTION of melatonin dosing for ASWPD - EARLY MORNING to produce a phase delay. This is the opposite of the evening dosing used in delayed sleep-wake phase disorder, and getting it backwards would worsen the disorder.

PMID:34493186 NO_EVIDENCE Other

"However, there is a lack of clinical data and information regarding the safety and effectiveness of melatonin"

Records the ABSENCE of clinical safety/efficacy data for melatonin in ASWPD. Classified NO_EVIDENCE rather than REFUTE because absence of data is not refutation - consistent with how the AASM guideline gap is recorded elsewhere in this treatment.

+ 2 more references

Schedule Accommodation and Sleep Scheduling

Action: behavioral and educational intervention Ontology label: Behavioral, Psychological or Informational Intervention NCIT:C63474

Where occupational and social circumstances permit, the simplest and often the most effective management is to accommodate the early schedule rather than fight it, since sleep is normal when taken at the biologically preferred time. Where a delay is required, a prescribed and consistently maintained later sleep-wake schedule may be attempted, typically alongside evening light. The AASM guideline made no recommendation on prescribed sleep scheduling or timed exercise for ASWPD because the evidence was insufficient. Health education and behavioral guidance for ASWPD explicitly includes AVOIDANCE OF BRIGHT LIGHT IN THE MORNING - the direction-critical negative instruction, since morning light sits on the phase-advance limb of the PRC and would worsen the disorder - alongside a midday nap, postponing bedtime, physical activity, and walking outdoors in the evening under bright light. Chronotherapy for ASWPD delays sleep onset progressively (by 3 hours every 2 days) until the desired later bedtime is reached; a single case maintained a 23:00 bedtime at 5-month follow-up.

Mechanism Target:

MODULATES Circadian Misalignment with Conventional Social Schedule — Aligning social demands with biological time removes the misalignment that generates morbidity, without altering the underlying clock.

Show evidence (4 references)

PMID:26414986 NO_EVIDENCE Human Clinical

"No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data."

Prescribed sleep scheduling and timed exercise for ASWPD are among the treatment/population combinations for which the AASM guideline could make no recommendation.

PMID:34493186 SUPPORT Other

"Health education and behavioral guidance can be given to patients, including the avoidance of bright light in the morning, taking a nap at noon, trying to postpone bedtime at night, performing physical activities, and walking in the evening under bright light."

Directly evidences the behavioral package for ASWPD, including the direction-critical instruction to AVOID morning bright light - the negative counterpart of evening light therapy.

PMID:34493186 PARTIAL Human Clinical

"the sleep onset time is delayed by 3 hours every 2 days until the sleep time is consistent with the desired later bedtime"

Gives the chronotherapy schedule specific to ASWPD (progressive DELAY, the opposite direction from DSWPD chronotherapy). Marked PARTIAL because the supporting clinical evidence is a single case report.

+ 1 more reference

🌍

Environmental Factors

3

Morning and Early-Day Light Exposure

Light is the dominant zeitgeber, and its effect is direction-dependent via the phase-response curve. Disproportionate light exposure in the early morning - the phase-advance portion of the curve - reinforces and stabilizes an already-advanced clock. This is the environmental counterpart of the disorder's mechanism and the reason morning bright light is contraindicated in ASPS even though it is therapeutic in delayed sleep-wake phase disorder.

Show evidence (1 reference)

PMID:21243069 SUPPORT Other

"Light is the strongest entraining agent of circadian rhythms and timed exposure to bright light is often used in the treatment of circadian rhythm sleep disorders."

Establishes light as the strongest entraining agent, whose timing determines the direction of the resulting phase shift.

Insufficient Evening Light Exposure

The converse exposure. Inadequate light in the evening removes the natural phase-delaying input that would otherwise oppose an advanced clock, allowing the advance to persist. Reduced evening activity and early retirement to a dark bedroom compound this, which is one reason the phenotype becomes more prominent after retirement and in institutionalized older adults.

Show evidence (2 references)

PMID:34493186 SUPPORT Other

"If an individual receives less light in the afternoon or evening, or is prematurely exposed to morning light following early awakening, the circadian rhythm can be advanced, leading to an increased risk of an early sleep phase"

Directly evidences both halves of the behavioral/environmental contribution - insufficient afternoon/evening light AND premature morning light exposure - as advancing the circadian rhythm and raising the risk of an early sleep phase. Note this also describes a self-reinforcing loop: early awakening leads to earlier light exposure, which further advances the clock.

PMID:39864932 PARTIAL Other

"Age-related alterations in circadian rhythms are exacerbated and compounded by neurodegenerative disorders, impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and light responsiveness in those affected."

Adds the age-related dimension - impaired light sensitivity and responsiveness. Marked PARTIAL because it addresses reduced light responsiveness rather than reduced evening light exposure specifically.

Rigid Conventional Social and Occupational Schedule

A non-photic environmental determinant of whether an advanced chronotype becomes a disorder. An early clock is only impairing when the person is required to be awake and functional in the evening or asleep past their spontaneous wake time. Schedules that permit early sleep and early rising render the same biology asymptomatic - which is also why ASPS is under-ascertained.

Show evidence (1 reference)

PMID:39864932 SUPPORT Other

"Advanced sleep phase (ASP) is seldom brought to medical attention because many individuals easily adapt to their early chronotype"

Supports that adaptability of the schedule determines whether the phenotype presents clinically at all.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Advanced Sleep Phase Syndrome:

Delayed Sleep-Wake Phase Disorder MONDO:0024377

Overlapping Features The mirror-image intrinsic circadian rhythm sleep-wake disorder, and by far the more commonly diagnosed of the two. Both are disorders of sleep timing with normal sleep when the preferred schedule is followed, and they share almost all of their clinical vocabulary - which is precisely why the literatures are easy to conflate. The direction of the phase shift is opposite and so is the treatment: DSWPD is treated with morning light and evening melatonin to advance the clock, ASPS with evening light to delay it. Applying DSWPD treatment to ASPS would worsen it.

Distinguishing Features

Sleep onset and offset are late (typically 02:00-06:00 onset) rather than early
Presenting complaint is sleep-onset insomnia and difficulty awakening in the morning, rather than evening sleepiness and early-morning awakening
Dim light melatonin onset (DLMO) is late rather than early
Onset is predominantly in adolescence rather than in early adulthood or with aging
Treatment direction is opposite - morning light and evening melatonin, versus evening light for ASPS

Show evidence (1 reference)

PMID:26414986 SUPPORT Human Clinical

"strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly..."

Shows that AASM issues DIFFERENT treatment recommendations for ASWPD (light therapy) and DSWPD (melatonin, plus light therapy only in children/adolescents) - concrete evidence that the two disorders are distinct and are not managed interchangeably.

Non-24-Hour Sleep-Wake Rhythm Disorder Not Yet Curated MONDO:0019137

Overlapping Features A circadian disorder in which the clock fails to entrain to the 24-hour day at all, so sleep timing drifts progressively later (or, rarely, earlier) day after day. Most common in totally blind individuals lacking photic input.

Distinguishing Features

Sleep timing progressively drifts rather than being stably advanced
Symptoms cycle between asymptomatic and symptomatic periods as the endogenous rhythm moves in and out of alignment
Actigraphy over several weeks shows a characteristic staircase pattern rather than a fixed early schedule
Strongly associated with total blindness and absent photic input

Show evidence (1 reference)

PMID:26414986 SUPPORT Human Clinical

"strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders)"

Confirms N24SWD as a separate intrinsic circadian disorder with its own (melatonin-based, blindness-associated) treatment recommendation, distinct from ASWPD.

Major Depressive Disorder with Early-Morning Awakening MONDO:0002009

Overlapping Features A clinically important differential in the opposite direction - terminal insomnia is a classic melancholic feature of major depression, and an ASPS patient reporting that they always wake at 4 a.m. is readily misread as depressed. Conversely, a depressed patient may be misclassified as having a circadian disorder. Getting this wrong matters because the treatments diverge completely, and because PER3-associated FASP is itself reported alongside elevated depression and seasonality scores, so the two can genuinely co-occur.

Distinguishing Features

Evening sleepiness is absent in depression; sleep onset is often delayed or unimpaired rather than involuntarily early
Sleep is nonrestorative in depression, whereas in ASPS it is restorative when taken at the preferred early hours
The whole circadian ensemble need not be phase-advanced in depression; DLMO is typically normal
Core depressive symptoms (anhedonia, low mood, guilt, appetite and psychomotor change) are present in depression and typically absent in ASPS

Show evidence (1 reference)

PMID:26903630 SUPPORT Human Clinical

"We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores."

Documents genuine co-occurrence of familial advanced sleep phase with depression scores, showing why the depression differential is both important and not always exclusive.

Insomnia Disorder Not Yet Curated MONDO:0013600

Overlapping Features Chronic insomnia is the most frequent misdiagnosis in ASPS, because the early-morning awakening is reported as terminal insomnia. This misclassification commonly leads to hypnotic prescription, which suppresses the symptom without correcting circadian phase and carries particular risk (falls, confusion, next-day impairment) in the older adults in whom advanced phase is most prevalent.

Distinguishing Features

In insomnia disorder sleep is poor regardless of when it is attempted; in ASPS sleep is normal once permitted at the advanced biological time
Sleep-onset latency is prolonged even at the preferred bedtime in insomnia disorder, but short in ASPS
A sleep diary showing consistently early, consolidated, restorative sleep on free days discriminates the two

Show evidence (1 reference)

PMID:34493186 SUPPORT Other

"CRSWDs are easily mistaken for insomnia or early waking up, resulting in inappropriate treatment."

Directly documents that circadian rhythm sleep-wake disorders are commonly misdiagnosed as insomnia, with inappropriate treatment as the consequence.

Irregular Sleep-Wake Rhythm Disorder Not Yet Curated MONDO:0024379

Overlapping Features Particularly relevant to the sporadic/age-related arm, since it arises in the same population - older adults, and especially those with dementia, in whom SCN degeneration is advanced. Whereas ASPS represents a coherent circadian rhythm shifted early, ISWRD represents loss of a consolidated rhythm altogether, with sleep fragmented into multiple bouts across the 24 hours. Sundowning and fragmented nocturnal sleep in dementia typically belong here rather than to ASPS.

Distinguishing Features

At least three irregular sleep episodes per 24-hour period, rather than one consolidated but early sleep episode
No stable phase relationship to clock time, so actigraphy shows fragmentation rather than a consistent early schedule
Total sleep across 24 hours may be normal but is not consolidated, whereas ASPS sleep is consolidated and normal in architecture
AASM gives it different treatment recommendations from ASWPD (melatonin in children/adolescents with comorbid neurological disorders; light therapy in elderly with dementia)

Show evidence (1 reference)

PMID:26414986 SUPPORT Human Clinical

"Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients"

Shows ISWRD in demented elderly patients attracts a recommendation AGAINST melatonin and hypnotics, the opposite management posture from ASWPD - so the distinction is clinically consequential.

Shift Work Disorder Not Yet Curated MONDO:0024382

Overlapping Features An extrinsic circadian disorder in which the misalignment is imposed by an externally mandated schedule rather than arising from the endogenous clock. Included because it is the standard exclusion when a patient reports sleep at unconventional hours, and because shift work and transmeridian travel were exclusion criteria in the major ASPS observational protocols.

Distinguishing Features

Caused by external behavioral/occupational factors rather than an intrinsic clock abnormality
Resolves or substantially improves when the imposed schedule is removed, whereas ASPS persists
Sleep timing follows the work roster rather than a stable early endogenous phase

Show evidence (1 reference)

PMID:34493186 SUPPORT Other

"extrinsic circadian rhythm sleep-wake disorders, in which sleep disorders, such as jet lag or shift-work disorder, result from environmental changes that cause a mismatch between sleep-wakefulness times and internal circadian rhythms"

Establishes the extrinsic/intrinsic distinction that separates shift work disorder (and jet lag) from ASPS, which is an intrinsic CRSWD.

Obstructive Sleep Apnea Syndrome MONDO:0007147

Overlapping Features Not a mimic so much as a confounder and frequent companion. Familial advanced sleep phase is most often discovered incidentally during evaluation for obstructive sleep apnea, and OSA independently causes fragmented sleep and daytime sleepiness that can obscure or be attributed to the circadian abnormality.

Distinguishing Features

OSA produces snoring, witnessed apneas, and sleep fragmentation with non-restorative sleep at any schedule
OSA is confirmed by polysomnography and does not shift circadian phase markers
The two frequently coexist, so identifying OSA does not exclude ASPS

Show evidence (1 reference)

PMID:39864932 SUPPORT Other

"is mostly discovered coincidentally in the presence of other sleep disorders, mainly obstructive sleep apnea syndrome (OSAS)"

Establishes OSA as the usual clinical context in which familial advanced sleep phase comes to attention.

🔬

Clinical Trials

2

NCT00246454 COMPLETED

Completed observational study (Northwestern University) of circadian rhythms and sleep propensity in familial advanced and familial delayed sleep phase syndrome. The largest ASPS-specific human cohort in this evidence set; ASPS inclusion required morning-type preference and an advanced melatonin onset.

Show evidence (1 reference)

clinicaltrials:NCT00246454 SUPPORT

"The purpose of this study is to determine the properties of circadian rhythms and sleep propensity in familial advanced and delayed sleep phase syndrome (DSPS)."

Directly establishes an ASPS-specific observational cohort characterizing circadian rhythms and sleep propensity in the familial form.

NCT04690504 COMPLETED

Completed biomarker-validation study (Brigham and Women's Hospital) comparing single-sample plasma-proteomic and monocyte-transcript estimates of circadian phase against melatonin phase in patients with circadian rhythm sleep disorders. Relevant to ASPS because the practical barrier to diagnosis and to correctly timed light therapy is the burden of serial DLMO sampling.

Show evidence (1 reference)

clinicaltrials:NCT04690504 SUPPORT

"The investigators aim to develop a method that can estimate individual circadian time with a single blood sample taken at any time of the day or night."

Establishes the aim of replacing burdensome serial circadian phase sampling with a single-sample estimate, the key translational bottleneck for circadian rhythm sleep disorders including ASPS.

{ }

Source YAML

click to show

name: Advanced Sleep Phase Syndrome
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
categories:
- Sleep Disorder
- Circadian Rhythm Sleep-Wake Disorder
- Circadian Timing Disorder
parents:
- Circadian Rhythm Sleep Disorder
- Sleep Disorder
disease_term:
  preferred_term: Advanced Sleep Phase Syndrome
  term:
    id: MONDO:0015609
    label: advanced sleep phase syndrome
description: >-
  Advanced sleep phase syndrome (ASPS), known in current sleep-medicine
  nomenclature as advanced sleep-wake phase disorder (ASWPD), is an intrinsic
  circadian rhythm sleep-wake disorder in which the endogenous circadian
  pacemaker is stably phase-advanced relative to the conventional light-dark
  and social cycle. Affected individuals fall asleep involuntarily in the early
  evening (typically 18:00-21:00) and wake spontaneously in the early morning
  (typically 02:00-05:00). The diagnostic key is that sleep itself is normal:
  when individuals are allowed to follow their own early schedule, sleep
  architecture, quality, and total duration are preserved. The complaint is
  therefore one of sleep timing, not sleep quality or quantity, and the
  clinical morbidity arises from the mismatch between biological and social
  time - evening sleepiness that truncates social and occupational activity,
  and early-morning awakening experienced as terminal insomnia when the person
  attempts to keep conventional hours.

  The familial form (familial advanced sleep phase syndrome, FASPS/FASP) is a
  landmark of human circadian genetics: it was the first well-characterized
  Mendelian circadian rhythm variant in humans and remains the clearest example
  of a single-gene lesion that changes a complex human behavior by changing the
  intrinsic period of the circadian clock. It segregates as an autosomal
  dominant trait with high penetrance and is caused by variants in components
  of the core transcription-translation feedback loop (TTFL) - PER2, CSNK1D,
  CRY2, PER3, and TIMELESS. A sporadic and age-related form also exists, in
  which advanced sleep timing emerges with aging and with neurodegenerative
  change in the suprachiasmatic nucleus.

  ASPS is substantially under-recognized relative to delayed sleep-wake phase
  disorder, in part because early rising is socially tolerated - even
  valorized - so affected individuals rarely present for care unless another
  sleep disorder brings them to attention.
has_subtypes:
- name: FASPS
  display_name: Familial Advanced Sleep Phase Syndrome (FASPS/FASP)
  description: >-
    The inherited form, segregating as an autosomal dominant trait with high
    penetrance. Typically emerges before age 30 and is present in a
    first-degree relative. Caused by variants in core circadian clock genes
    (PER2, CSNK1D, CRY2, PER3, TIMELESS) that shorten the intrinsic circadian
    period or alter photic entrainment. This is the form to which the MONDO
    concept and its familial advanced sleep-phase syndrome synonyms most
    directly correspond, and it is the mechanistic centrepiece of this entry.
  classification: etiologic
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe three kindreds with a profound phase advance of the
      sleep-wake, melatonin and temperature rhythms associated with a very
      short tau. The trait segregates as an autosomal dominant with high
      penetrance.
    explanation: >-
      The original description of FASPS establishes the autosomal dominant,
      highly penetrant familial subtype with a short intrinsic period.
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Advanced sleep phase (ASP) is seldom brought to medical attention because
      many individuals easily adapt to their early chronotype, especially if it
      emerges before the age of 30 and is present in a first-degree relative.
      In this case, the disorder is considered familial (FASP)
    explanation: >-
      Defines the familial subtype by early onset plus a first-degree relative,
      and notes its characteristic under-ascertainment.
- name: Sporadic/Age-Related ASPS
  display_name: Sporadic and Age-Related Advanced Sleep Phase
  description: >-
    The non-familial form, in which advanced sleep timing arises without an
    identified Mendelian variant. Advanced sleep timing becomes progressively
    more common with age, and age-related circadian change is compounded by
    neurodegenerative disease affecting the suprachiasmatic nucleus and by
    reduced sensitivity and responsiveness to light. Early morning awakening
    occurs in roughly 4% of older individuals, and distressing advanced
    sleep-wake timing (ASWPD) affects approximately 1% of middle-aged adults.
  classification: etiologic
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Early morning awakening is, instead, more common among older individuals,
      occurring in almost 4% of cases, without considering associated
      comorbidities. Advanced sleep-wake phase disorder (ASWPD) is
      characterized by a consistent and distressing anticipation of sleep-wake
      timing, affecting almost 1% of middle-aged individuals.
    explanation: >-
      Distinguishes the age-related/sporadic form and quantifies early morning
      awakening in older adults and ASWPD in middle age.
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Age-related alterations in circadian rhythms are exacerbated and
      compounded by neurodegenerative disorders, impacting the suprachiasmatic
      nucleus (SCN), sensitivity to light, and light responsiveness in those
      affected.
    explanation: >-
      Identifies the SCN and photic-responsiveness substrate of the age-related
      subtype, distinguishing it mechanistically from the Mendelian form.
pathophysiology:
- name: Age-Related Suprachiasmatic Nucleus Decline
  description: >-
    The trigger of the SPORADIC / AGE-RELATED arm, mechanistically distinct
    from the Mendelian arm. With advancing age - and compounded by
    neurodegenerative disease - the suprachiasmatic nucleus itself is affected,
    reducing the robustness and amplitude of central pacemaker output. This is
    a degenerative/structural route to an unstable, easily-advanced clock
    rather than a change in the kinetics of the molecular oscillator, and it
    explains why advanced sleep timing becomes progressively more common with
    age. It is the arm that accounts for the substantially higher
    population-level prevalence figures (approximately 1% of middle-aged
    adults, and early morning awakening in about 4% of older individuals)
    relative to the rare Mendelian kindreds.
  biological_scale: CELLULAR
  role: trigger
  subtypes:
  - Sporadic/Age-Related ASPS
  cell_types:
  - preferred_term: Suprachiasmatic nucleus pacemaker neuron
    term:
      id: CL:4072019
      label: SCN pacemaker neuron
  biological_processes:
  - preferred_term: Regulation of circadian rhythm
    term:
      id: GO:0042752
      label: regulation of circadian rhythm
    modifier: DECREASED
  locations:
  - preferred_term: Suprachiasmatic nucleus
    term:
      id: UBERON:0002034
      label: suprachiasmatic nucleus
  downstream:
  - target: Reduced Photic Sensitivity and Light Responsiveness
    causal_link_type: DIRECT
    description: >-
      SCN decline is accompanied by reduced sensitivity and responsiveness to
      the entraining light signal.
  - target: Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced pacemaker amplitude and robustness permit a drift to an earlier
      phase, independently of any change in intrinsic period.
    intermediate_mechanisms:
    - Reduced amplitude and robustness of SCN pacemaker output
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Age-related alterations in circadian rhythms are exacerbated and
      compounded by neurodegenerative disorders, impacting the suprachiasmatic
      nucleus (SCN), sensitivity to light, and light responsiveness in those
      affected.
    explanation: >-
      Directly identifies the SCN as the anatomical substrate of the
      age-related arm, and names neurodegenerative disease as an exacerbating
      factor.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A large survey of a middle-aged and elderly population (40~64 years old)
      showed that the prevalence of ASWPD was approximately 1%, and increased
      with age; however, no gender differences were found
    explanation: >-
      Establishes the age-dependence of ASWPD prevalence, the epidemiological
      signature of this non-Mendelian arm.
  notes: >-
    The direction of the association between ASWPD and cognitive decline is
    NOT settled. PMID:39864932 reports "Conflicting data has surfaced regarding
    the protective or detrimental effects of ASWPD in studies on aging, mild
    cognitive impairment (MCI), and diverse dementia conditions." This node
    therefore models age/neurodegeneration as an upstream contributor to
    advanced phase, and deliberately does NOT assert a downstream effect of
    advanced phase on cognition.
- name: Reduced Photic Sensitivity and Light Responsiveness
  description: >-
    The mediating step of the sporadic/age-related arm. Ageing reduces both the
    sensitivity of the circadian system to light and its responsiveness to it -
    through the SCN and its input pathway - so the daily zeitgeber signal that
    normally holds the clock at the correct phase is weakened. A weakened
    entraining signal is less able to oppose a drift toward earlier timing, and
    it also blunts the response to the evening light used therapeutically,
    which is part of why light therapy is harder to deliver effectively in
    exactly the older population in which this arm predominates.

    A behavioral positive-feedback loop compounds this: early awakening leads
    to premature morning light exposure, which falls on the phase-advance limb
    of the phase-response curve and advances the clock further.
  biological_scale: CELLULAR
  role: mediator
  subtypes:
  - Sporadic/Age-Related ASPS
  cell_types:
  - preferred_term: Intrinsically photosensitive retinal ganglion cell
    term:
      id: CL:0020014
      label: intrinsically photosensitive retinal ganglion cell
  biological_processes:
  - preferred_term: Entrainment of circadian clock by photoperiod
    term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
    modifier: DECREASED
  locations:
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  downstream:
  - target: Altered Photic Entrainment of the Circadian Pacemaker
    causal_link_type: DIRECT
    description: >-
      A weakened photic input degrades entrainment, converging on the same
      node through which the Mendelian TIMELESS and CRY2 lesions act.
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and
      light responsiveness in those affected
    explanation: >-
      Names reduced sensitivity to light and reduced light responsiveness
      explicitly as components of the age-related circadian alteration.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If an individual receives less light in the afternoon or evening, or is
      prematurely exposed to morning light following early awakening, the
      circadian rhythm can be advanced, leading to an increased risk of an
      early sleep phase
    explanation: >-
      Evidences the behavioral positive-feedback loop - early awakening brings
      forward light exposure, which advances the clock further.
- name: Autosomal Dominant Core Clock Gene Variant
  description: >-
    A germline, autosomal dominant variant in a component of the core circadian
    transcription-translation feedback loop (TTFL) or its regulatory kinase.
    In the canonical loop, CLOCK-BMAL1 activates transcription of PER and CRY;
    PER/CRY protein complexes accumulate, are phosphorylated, enter the
    nucleus, and repress CLOCK-BMAL1. The rate constants of this loop -
    phosphorylation, degradation, and nuclear entry - set the intrinsic period
    (tau). FASPS variants perturb exactly these rate constants. Reported genes
    are PER2, CSNK1D, CRY2, PER3, and TIMELESS.
  biological_scale: MOLECULAR
  role: trigger
  subtypes:
  - FASPS
  cell_types:
  - preferred_term: Suprachiasmatic nucleus pacemaker neuron
    term:
      id: CL:4072019
      label: SCN pacemaker neuron
  biological_processes:
  - preferred_term: Circadian rhythm
    term:
      id: GO:0007623
      label: circadian rhythm
  - preferred_term: Circadian regulation of gene expression
    term:
      id: GO:0032922
      label: circadian regulation of gene expression
  genes:
  - preferred_term: PER2
    term:
      id: hgnc:8846
      label: PER2
  - preferred_term: CSNK1D
    term:
      id: hgnc:2452
      label: CSNK1D
  - preferred_term: CRY2
    term:
      id: hgnc:2385
      label: CRY2
  - preferred_term: PER3
    term:
      id: hgnc:8847
      label: PER3
  - preferred_term: TIMELESS
    term:
      id: hgnc:11813
      label: TIMELESS
  locations:
  - preferred_term: Suprachiasmatic nucleus
    term:
      id: UBERON:0002034
      label: suprachiasmatic nucleus
  downstream:
  - target: PER2 CK1-Site Hypophosphorylation
    causal_link_type: DIRECT
    description: PER2 S662G removes the CK1delta/epsilon phosphoacceptor serine.
  - target: CK1delta Reduced Kinase Activity
    causal_link_type: DIRECT
    description: CSNK1D T44A reduces the enzymatic activity of the kinase itself.
  - target: CRY2 Destabilization by FBXL3
    causal_link_type: DIRECT
    description: CRY2 A260T increases FBXL3 affinity and CRY2 turnover.
  - target: TIMELESS Nuclear Exclusion
    causal_link_type: DIRECT
    description: A TIMELESS mutation prevents nuclear accumulation of TIM.
  - target: PER3 Destabilization
    causal_link_type: DIRECT
    description: PER3 P415A/H417R destabilizes PER3 protein.
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal dominant mutations in circadian clock genes like PER2, CK1,
      PER3, CRY2, TIMELESS, and DEC2 have been linked to FASP, some with
      pleiotropic effects influencing other health aspects like migraine and
      depression.
    explanation: >-
      Review enumerates the autosomal dominant core clock genes implicated in
      familial advanced sleep phase.
  - reference: PMID:31400754
    reference_title: "Genetics of the human circadian clock and sleep homeostat."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A portion of the variation in the population is controlled by genetics as
      shown by the single-gene mutations that confer extreme early or late
      chronotypes.
    explanation: >-
      Establishes that single-gene clock mutations are sufficient to produce
      extreme early chronotype, the genetic premise of this node.
- name: PER2 CK1-Site Hypophosphorylation
  description: >-
    The original FASPS lesion, PER2 p.Ser662Gly (S662G), substitutes glycine
    for a serine that lies within the casein kinase I epsilon/delta binding
    region of hPER2 and is itself a CK1 phosphoacceptor. Loss of this
    phosphoacceptor causes PER2 to be hypophosphorylated by CK1 in vitro.
    Because CK1-dependent phosphorylation of PER2 governs both PER2
    transcriptional feedback and PER2 protein turnover, the substitution
    retunes the feedback loop and alters the circadian period. This is the
    substrate side of the PER2/CK1delta lesion pair.
  biological_scale: MOLECULAR
  role: central_effector
  biological_processes:
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  - preferred_term: Regulation of circadian rhythm
    term:
      id: GO:0042752
      label: regulation of circadian rhythm
  genes:
  - preferred_term: PER2
    term:
      id: hgnc:8846
      label: PER2
  downstream:
  - target: Altered PER/CRY Negative Feedback on CLOCK-BMAL1
    causal_link_type: DIRECT
    description: >-
      Hypophosphorylated PER2 alters the timing and strength of PER/CRY
      repression of CLOCK-BMAL1.
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals have a serine to glycine mutation within the casein
      kinase Iepsilon (CKIepsilon) binding region of hPER2
    explanation: >-
      Human genetic finding - establishes the serine-to-glycine substitution in
      the CK1epsilon binding region of hPER2 in affected individuals.
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      which causes hypophosphorylation by CKIepsilon in vitro
    explanation: >-
      Biochemical finding, split from the human genetic item above because the
      authors state the hypophosphorylation result is in vitro. This is the
      evidence for the phosphorylation defect itself.
  - reference: PMID:17218255
    reference_title: "Modeling of a human circadian mutation yields insights into clock regulation by PER2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated transgenic mice carrying the FASPS hPER2 S662G mutation and
      faithfully recapitulate the human phenotype. We show that phosphorylation
      at S662 leads to increased PER2 transcription and suggest that
      phosphorylation at another site leads to PER2 degradation.
    explanation: >-
      Mouse modelling of S662G recapitulates the human phenotype and shows the
      phosphosite controls PER2 transcription and, at other sites, degradation.
- name: CK1delta Reduced Kinase Activity
  description: >-
    CSNK1D p.Thr44Ala (T44A) mutates the kinase rather than the substrate:
    casein kinase I delta acts on the same PER2 phosphorylation axis that is
    disrupted by PER2 S662G. (The published evidence for the linkage is
    dosage epistasis - altering CKIdelta dosage modulates the S662 phenotype -
    rather than a direct demonstration that CK1delta phosphorylates residue
    662 itself.) The T44A mutant kinase has decreased enzymatic
    activity in vitro. This is the enzyme side of the same molecular lesion,
    and it phenocopies PER2 S662G - a strikingly clean piece of mechanistic
    evidence, because the substrate lesion and the kinase lesion converge on a
    single biochemical event (CK1-dependent PER2 phosphorylation) and produce
    the same human phenotype. Transgenic mice bearing CKIdelta-T44A have a
    shortened circadian period mimicking human FASPS, and CKIdelta gene dosage
    modulates the PER2 S662G phenotype in vivo, formally demonstrating that the
    two lesions act on the same axis.
  biological_scale: MOLECULAR
  role: central_effector
  biological_processes:
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  genes:
  - preferred_term: CSNK1D
    term:
      id: hgnc:2452
      label: CSNK1D
  downstream:
  - target: PER2 CK1-Site Hypophosphorylation
    causal_link_type: DIRECT
    description: >-
      Reduced CK1delta enzymatic activity produces the same end state as loss
      of the PER2 phosphoacceptor serine - hypophosphorylated PER2. This is the
      kinase-side-to-substrate-side convergence that makes the PER2/CSNK1D
      pair unusually strong mechanistic evidence.
    evidence:
    - reference: PMID:17218255
      reference_title: "Modeling of a human circadian mutation yields insights into clock regulation by PER2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Altering CKIdelta dosage modulates the S662 phenotype demonstrating
        that CKIdelta can regulate period through PER2 in vivo.
      explanation: >-
        Genetic-dosage evidence that CK1delta acts on circadian period through
        PER2 specifically, directly supporting the kinase to substrate edge.
  evidence:
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the identification of a missense mutation (T44A) in the
      human CKIdelta gene, which results in FASPS.
    explanation: >-
      Human genetic finding - establishes CSNK1D T44A as a FASPS-causing
      variant.
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutant kinase has decreased enzymatic activity in vitro.
    explanation: >-
      Biochemical finding, split from the human genetic item above because the
      authors state the reduced kinase activity is an in vitro result. This is
      the evidence for the enzymatic defect itself.
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, transgenic mice carrying the same mutation have a shorter
      circadian period, a phenotype mimicking human FASPS.
    explanation: >-
      Mouse model of CKIdelta T44A shows the period shortening that underlies
      the human phase advance. Note the accompanying Drosophila transgenic
      showed a lengthened period, so the direction of effect is
      species-dependent and the mammalian model is the relevant one.
- name: CRY2 Destabilization by FBXL3
  description: >-
    CRY2 p.Ala260Thr (A260T) lies in the phosphate loop of the FAD-binding
    domain of CRY2. The substitution changes CRY2 conformation so as to
    increase its accessibility and affinity for FBXL3, an E3 ubiquitin ligase,
    thereby promoting CRY2 ubiquitination and degradation. Accelerated turnover
    of this negative-limb repressor shortens the circadian period.
  biological_scale: MOLECULAR
  role: central_effector
  biological_processes:
  - preferred_term: Protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: INCREASED
  - preferred_term: Protein destabilization
    term:
      id: GO:0031648
      label: protein destabilization
    modifier: INCREASED
  genes:
  - preferred_term: CRY2
    term:
      id: hgnc:2385
      label: CRY2
  downstream:
  - target: Altered PER/CRY Negative Feedback on CLOCK-BMAL1
    causal_link_type: DIRECT
    description: Accelerated CRY2 degradation weakens and shortens repression.
  - target: Altered Photic Entrainment of the Circadian Pacemaker
    causal_link_type: DIRECT
    description: >-
      The CRY2 variant additionally reduces the phase-shifting response to an
      early-night light pulse, so it acts on the entrainment arm as well as on
      period - the two routes are not mutually exclusive.
    evidence:
    - reference: PMID:27529127
      reference_title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In mice, the CRY2 mutation causes a shortened circadian period and
        reduced phase-shift to early-night light pulse associated with
        phase-advanced behavioral rhythms in the light-dark cycle.
      explanation: >-
        Explicitly reports a reduced phase-shift to an early-night light pulse,
        establishing that CRY2 A260T also perturbs photic entrainment.
  evidence:
  - reference: PMID:27529127
    reference_title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene
      that co-segregates with FASP in one family. The mutation leads to
      replacement of an alanine residue at position 260 with a threonine
      (A260T).
    explanation: >-
      Establishes CRY2 A260T co-segregating with familial advanced sleep phase.
  - reference: PMID:27529127
    reference_title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutation alters the conformation of CRY2, increasing its
      accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus
      promoting its degradation.
    explanation: >-
      Directly establishes the FBXL3-mediated degradation mechanism for the
      A260T variant.
- name: TIMELESS Nuclear Exclusion
  description: >-
    A mutation in human TIMELESS (hTIM) prevents TIM from accumulating in the
    nucleus and alters its affinity for CRY2, destabilizing the PER/CRY complex
    and weakening repression of CLOCK-BMAL1. Notably, this variant produces
    advanced sleep phase primarily by altering photic entrainment rather than
    by shortening the organismal period: CRISPR mutant mice show advanced sleep
    phase with altered photic entrainment but a normal circadian period, even
    though period shortening is seen in mutant fibroblasts. What distinguishes
    TIMELESS from the other FASPS lesions is specifically the NORMAL organismal
    period - entrainment involvement as such is not unique to it, since the
    CRY2 A260T variant also shows a reduced phase-shift to early-night light
    while additionally shortening period.
  biological_scale: MOLECULAR
  role: mediator
  biological_processes:
  - preferred_term: Protein import into nucleus
    term:
      id: GO:0006606
      label: protein import into nucleus
    modifier: DECREASED
  - preferred_term: Entrainment of circadian clock by photoperiod
    term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
  genes:
  - preferred_term: TIMELESS
    term:
      id: hgnc:11813
      label: TIMELESS
  downstream:
  - target: Altered PER/CRY Negative Feedback on CLOCK-BMAL1
    causal_link_type: DIRECT
    description: Cytoplasmic TIM destabilizes the PER/CRY repressor complex.
  - target: Altered Photic Entrainment of the Circadian Pacemaker
    causal_link_type: DIRECT
    description: >-
      The dominant route for this variant - altered phase responsiveness to
      light rather than a shortened intrinsic period.
  evidence:
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a mutation in the human TIMELESS (hTIM) gene that causes
      familial advanced sleep phase (FASP).
    explanation: Establishes TIMELESS as a FASP gene in humans.
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that the mutation prevents TIM accumulation in the nucleus
      and has altered affinity for CRY2, leading to destabilization of PER/CRY
      complex and a shortened period in nonmature mouse embryonic fibroblasts
      (MEFs).
    explanation: >-
      Establishes nuclear exclusion, altered CRY2 affinity, and PER/CRY
      destabilization as the molecular consequence.
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but
      normal circadian period.
    explanation: >-
      Qualifies the mechanism - for TIMELESS the organismal phenotype arises via
      altered photic entrainment, not via a shortened organismal period. This
      is why the entry models a separate entrainment branch.
- name: PER3 Destabilization
  description: >-
    Two rare PER3 variants (p.Pro415Ala and p.His417Arg, PER3-P415A/H417R) were
    identified in individuals with familial advanced sleep phase who also had
    higher Beck Depression Inventory and seasonality scores. The variants
    destabilize PER3 and fail to stabilize PER1/PER2 proteins. The evidence
    base here is weaker than for PER2 or CSNK1D - a single kindred with a
    two-variant haplotype, and the human phenotype is co-reported with a mood
    trait rather than isolated phase advance - so this node is curated as a
    contributory rather than an established mechanism.
  biological_scale: MOLECULAR
  role: modifier
  biological_processes:
  - preferred_term: Protein destabilization
    term:
      id: GO:0031648
      label: protein destabilization
    modifier: INCREASED
  genes:
  - preferred_term: PER3
    term:
      id: hgnc:8847
      label: PER3
  downstream:
  - target: Altered PER/CRY Negative Feedback on CLOCK-BMAL1
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      PER3 destabilization removes stabilizing support for PER1/PER2, the
      direct repressor-limb components.
    intermediate_mechanisms:
    - PER1/PER2 protein destabilization
  evidence:
  - reference: PMID:26903630
    reference_title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two rare variants in the circadian clock gene PERIOD3
      (PER3-P415A/H417R) in humans with familial advanced sleep phase
      accompanied by higher Beck Depression Inventory and seasonality scores.
    explanation: >-
      Establishes the PER3 variants in familial advanced sleep phase, with the
      important caveat that the phenotype was co-reported with a mood trait.
  - reference: PMID:26903630
    reference_title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Molecular characterization revealed that the rare variants destabilized
      PER3 and failed to stabilize PERIOD1/2 proteins, which play critical
      roles in circadian timing.
    explanation: >-
      Provides the destabilization mechanism and its link to PER1/PER2, the
      intermediate in the causal edge.
- name: Altered PER/CRY Negative Feedback on CLOCK-BMAL1
  description: >-
    All of the established FASPS lesions converge here. The TTFL keeps time
    because PER/CRY repressor complexes accumulate, are post-translationally
    delayed, enter the nucleus, repress CLOCK-BMAL1, and are then degraded,
    permitting the next cycle. Reducing the delay - by hypophosphorylating PER2
    (PER2 S662G, CSNK1D T44A), by accelerating CRY2 degradation (CRY2 A260T),
    or by destabilizing the PER/CRY complex (TIMELESS, PER3) - makes each
    iteration of the loop complete faster. This is the shared molecular
    convergence point of the disorder.
  biological_scale: MOLECULAR
  role: central_effector
  biological_processes:
  - preferred_term: Circadian regulation of gene expression
    term:
      id: GO:0032922
      label: circadian regulation of gene expression
  - preferred_term: PER/CRY transcriptional repression of CLOCK-BMAL1
    term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
  downstream:
  - target: Shortened Intrinsic Circadian Period
    causal_link_type: DIRECT
    description: A faster feedback loop yields a shorter free-running period.
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, a variant in human sleep behavior can be attributed to a missense
      mutation in a clock component, hPER2, which alters the circadian period.
    explanation: >-
      Establishes that a clock-component variant acts by altering the circadian
      period, the output of this convergence node.
- name: Altered Photic Entrainment of the Circadian Pacemaker
  description: >-
    Light reaching intrinsically photosensitive retinal ganglion cells is
    conveyed by the retinohypothalamic tract to the suprachiasmatic nucleus and
    is the dominant zeitgeber that entrains the clock to the 24-hour day. The
    direction of the resulting shift depends on when in the circadian cycle the
    light falls (the phase-response curve): light in the late night/early
    morning advances the clock, light in the evening delays it. A clock lesion
    can therefore advance phase either by shortening period or by biasing this
    entrainment response, and the TIMELESS variant acts predominantly through
    the latter. This node is also the substrate on which treatment acts, and
    the reason mistimed light worsens the disorder.
  biological_scale: CELLULAR
  role: mediator
  cell_types:
  - preferred_term: Intrinsically photosensitive retinal ganglion cell
    term:
      id: CL:0020014
      label: intrinsically photosensitive retinal ganglion cell
  biological_processes:
  - preferred_term: Entrainment of circadian clock by photoperiod
    term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
  locations:
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: Suprachiasmatic nucleus
    term:
      id: UBERON:0002034
      label: suprachiasmatic nucleus
  downstream:
  - target: Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
    causal_link_type: DIRECT
    description: Biased entrainment settles the clock at an abnormally early phase.
  evidence:
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that TIM, when excluded from the nucleus, can destabilize the
      negative regulators of the circadian clock, alter light entrainment, and
      cause FASP.
    explanation: >-
      Establishes altered light entrainment as a distinct causal route to
      familial advanced sleep phase.
  - reference: PMID:21243069
    reference_title: "Therapeutics for Circadian Rhythm Sleep Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Light is the strongest entraining agent of circadian rhythms and timed
      exposure to bright light is often used in the treatment of circadian
      rhythm sleep disorders.
    explanation: >-
      Establishes light as the dominant entraining agent and the basis of
      timed-light therapy acting on this node.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Studies have also shown that morning light can advance, while evening
      light or light before bedtime can delay the phase of the circadian
      rhythm
    explanation: >-
      Directly evidences the DIRECTIONALITY of the phase-response curve that
      this node asserts, and which underpins both the pathophysiology (morning
      light reinforces an advance) and the treatment (evening light corrects
      it). This is the sentence that makes the ASWPD-versus-DSWPD mirror-image
      logic evidentiable rather than merely asserted.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A phase response curve (PRC) has been generated to describe the magnitude
      and direction of the phase shift of the circadian rhythm according to the
      time, duration, and intensity of light exposure
    explanation: >-
      Establishes the phase-response curve itself as the formal construct
      governing the magnitude and direction of light-induced phase shifts.
- name: Shortened Intrinsic Circadian Period
  description: >-
    The hallmark physiological abnormality of Mendelian FASPS - a free-running
    circadian period (tau) measurably shorter than the normal ~24.2 hours. A
    clock that runs fast must be reset backwards each day by the zeitgeber; the
    steady-state consequence of entraining a short-period oscillator to a
    24-hour day is that it settles at an abnormally early phase angle. This is
    the direct mechanistic explanation for why a period abnormality produces a
    phase abnormality, and it is the reason FASPS individuals are
    phase-advanced rather than simply free-running.
  biological_scale: CELLULAR
  role: central_effector
  biological_processes:
  - preferred_term: Circadian rhythm
    term:
      id: GO:0007623
      label: circadian rhythm
  - preferred_term: Regulation of circadian rhythm
    term:
      id: GO:0042752
      label: regulation of circadian rhythm
  locations:
  - preferred_term: Suprachiasmatic nucleus
    term:
      id: UBERON:0002034
      label: suprachiasmatic nucleus
  downstream:
  - target: Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
    causal_link_type: DIRECT
    description: >-
      A short-period oscillator entrained to a 24-hour day stabilizes at an
      advanced phase angle of entrainment.
  evidence:
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe three kindreds with a profound phase advance of the
      sleep-wake, melatonin and temperature rhythms associated with a very
      short tau.
    explanation: >-
      Directly links the short intrinsic period (tau) to the profound phase
      advance in humans.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Autosomal semi-dominant mutations in rodents with fast or slow biological
      clocks (that is, short or long endogenous period lengths; tau) are
      associated with phase-advanced or delayed sleep-wake rhythms,
      respectively.
    explanation: >-
      States the general period-to-phase principle established in rodents that
      predicted, and explains, the human phenotype.
  - reference: PMID:27529127
    reference_title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, the CRY2 mutation causes a shortened circadian period and
      reduced phase-shift to early-night light pulse associated with
      phase-advanced behavioral rhythms in the light-dark cycle.
    explanation: >-
      Independent genetic confirmation that period shortening produces
      phase-advanced behavioral rhythms.
- name: Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
  description: >-
    The integrated organism-level output - the entire circadian ensemble,
    pineal melatonin secretion, core body temperature nadir, and the circadian
    drive for sleep, is displaced several hours earlier than normal. In the
    original FASPS kindreds this amounted to roughly a 4-hour advance of the
    sleep, temperature, and melatonin rhythms. Crucially, the oscillation
    itself is intact and of normal amplitude; only its phase is shifted. This
    is why sleep architecture and duration remain normal, and why the disorder
    is one of timing rather than of sleep quality.
  biological_scale: ORGANISM
  role: effector
  biological_processes:
  - preferred_term: Circadian sleep/wake cycle
    term:
      id: GO:0042745
      label: circadian sleep/wake cycle
  - preferred_term: Circadian behavior
    term:
      id: GO:0048512
      label: circadian behavior
  locations:
  - preferred_term: Pineal body
    term:
      id: UBERON:0001905
      label: pineal body
  downstream:
  - target: Early Chronotype
    causal_link_type: DIRECT
  - target: Advanced Melatonin Secretion Phase
    causal_link_type: DIRECT
    description: >-
      The pineal melatonin rhythm is one component of the displaced circadian
      ensemble, and the one used clinically as the phase marker (DLMO).
  - target: Early Evening Sleep Onset
    causal_link_type: DIRECT
  - target: Early Morning Awakening
    causal_link_type: DIRECT
  - target: Evening Sleepiness
    causal_link_type: DIRECT
  - target: Preserved Sleep Quality and Duration on a Self-Selected Schedule
    causal_link_type: DIRECT
    description: >-
      Because only phase, not oscillator integrity, is disturbed, sleep is
      normal when permitted to occur at the advanced biological time.
  - target: Circadian Misalignment with Conventional Social Schedule
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant
      circadian rhythm variant; affected individuals are "morning larks" with a
      4-hour advance of the sleep, temperature, and melatonin rhythms.
    explanation: >-
      Quantifies the coordinated multi-marker phase advance that defines this
      node.
- name: Circadian Misalignment with Conventional Social Schedule
  description: >-
    The clinically disabling step. An advanced clock is not intrinsically
    harmful; morbidity arises when biological night conflicts with the socially
    required schedule. Attempting to stay awake for evening obligations
    produces overwhelming evening sleepiness; attempting to remain asleep to a
    conventional wake time produces early-morning awakening experienced as
    terminal insomnia; and resisting the advanced schedule at both ends causes
    chronic sleep restriction. Distress or functional impairment arising from
    this misalignment - not the early timing per se - is what converts an
    advanced chronotype into advanced sleep-wake phase disorder.
  biological_scale: ORGANISM
  role: outcome
  downstream:
  - target: Sleep Restriction and Functional Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The main clinical manifestations are insomnia and excessive daytime
      sleepiness that often lead to clinically meaningful distress or cause
      mental, physical, social, occupational, educational, or other functional
      impairment.
    explanation: >-
      Establishes that clinically meaningful distress and functional impairment
      define the disorder-level presentation of circadian misalignment.
  - reference: PMID:31400754
    reference_title: "Genetics of the human circadian clock and sleep homeostat."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Negative health consequences have been identified when individuals do not
      sleep at their ideal circadian timing or are sleep deprived relative to
      intrinsic sleep need.
    explanation: >-
      Supports that harm follows from sleeping away from one's ideal circadian
      timing, i.e. from misalignment rather than from the phase itself.
phenotypes:
- name: Early Chronotype
  category: Behavioral
  description: >-
    A stable, lifelong tendency to rise very early and to go to bed early - the
    morning lark extreme of the chronotype distribution. In FASPS this is
    profound rather than a mild preference, and is present in multiple
    generations of a kindred.
  phenotype_term:
    preferred_term: Early chronotype
    term:
      id: HP:0031873
      label: Early chronotype
    clinical_course: STABLE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals are "morning larks" with a 4-hour advance of the
      sleep, temperature, and melatonin rhythms
    explanation: >-
      Describes the extreme morning chronotype that defines affected
      individuals.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although a slight 'morning lark' tendency is common, individuals with a
      large and disabling sleep phase-advance are rare.
    explanation: >-
      Distinguishes the disabling extreme chronotype of ASPS from the common
      mild morning preference.
- name: Early Evening Sleep Onset
  category: Behavioral
  description: >-
    Involuntary sleep onset in the early evening, typically between 18:00 and
    21:00, several hours earlier than the socially conventional bedtime. Sleep
    onset latency is short and sleep initiation is not impaired - this is not
    sleep-onset insomnia but a clock set early.
  phenotype_term:
    preferred_term: Advanced sleep onset
    term:
      id: HP:0031873
      label: Early chronotype
    temporality: CHRONIC
  notes: >-
    NEEDS TERM (NTR candidate). This phenotype shares HP:0031873 with
    `Early Chronotype`, but the two are distinct claims: HP:0031873 is defined
    as "A tendency towards rising very early in the morning and going to bed
    early in the evening" - a stable trait disposition - whereas this row
    asserts the specific clock-time observation of involuntary sleep onset in
    the early evening. "Advanced sleep onset" is an EXACT synonym of
    HP:0031873, so it is the correct available binding, and the alternative
    (the grandparent HP:0006979 Sleep-wake cycle disturbance) is
    direction-neutral and would fit delayed sleep phase equally well. A
    distinct HPO child term for advanced sleep onset would resolve the reuse.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial advanced sleep phase syndrome (FASPS) is a human behavioural
      phenotype characterized by early sleep times and early-morning awakening.
    explanation: >-
      Directly documents early sleep times as a defining clinical feature.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disorder, advanced sleep-phase syndrome, is characterized by very
      early sleep onset and offset
    explanation: >-
      Defines very early sleep onset as a core characteristic of the disorder.
- name: Early Morning Awakening
  category: Behavioral
  description: >-
    Spontaneous final awakening in the early morning hours, typically between
    02:00 and 05:00, with inability to return to sleep. When the individual is
    attempting to keep a conventional schedule this is experienced and often
    misreported as terminal (late) insomnia, which is a major reason ASPS is
    misdiagnosed as an insomnia disorder or as depression.
  phenotype_term:
    preferred_term: Terminal insomnia
    term:
      id: HP:0031356
      label: Terminal insomnia
    temporality: CHRONIC
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial advanced sleep phase syndrome (FASPS) is a human behavioural
      phenotype characterized by early sleep times and early-morning
      awakening.
    explanation: >-
      Directly documents early-morning awakening as a defining clinical
      feature.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CRSWDs are easily mistaken for insomnia or early waking up, resulting in
      inappropriate treatment.
    explanation: >-
      Supports that the early awakening of a circadian disorder is commonly
      misattributed to an insomnia disorder, leading to inappropriate therapy.
- name: Evening Sleepiness
  category: Behavioral
  description: >-
    Overwhelming sleepiness in the late afternoon and evening, worsening when
    the individual attempts to remain awake for social, family, or occupational
    obligations. Unlike the excessive daytime somnolence of a primary
    hypersomnia, it is confined to the biological evening and resolves if sleep
    is permitted at the advanced time.
  phenotype_term:
    preferred_term: Evening drowsiness
    term:
      id: HP:0002329
      label: Drowsiness
    temporality: DIURNAL
  notes: >-
    `frequency:` is deliberately omitted. The cited source reports no
    per-symptom frequency data for evening sleepiness, and no quantitative
    frequency band could be justified from the available abstracts. Per the
    project frequency-evidence guidelines, omission is preferred to a
    fabricated band.
  evidence:
  - reference: PMID:31384946
    reference_title: "Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This can optimize treatment for evening sleepiness and early morning
      awakening
    explanation: >-
      Identifies evening sleepiness (paired with early morning awakening) as
      the treatable symptom complex of extreme advanced chronotypes. Marked
      PARTIAL because this is a conclusions-section statement about treatment
      targets in a prevalence study, not a direct observation of the phenotype
      or its frequency.
- name: Preserved Sleep Quality and Duration on a Self-Selected Schedule
  category: Behavioral
  description: >-
    The single most useful discriminating feature. When affected individuals
    are permitted to sleep at their own early hours, sleep is consolidated and
    of normal architecture, quality, and total duration. This distinguishes
    ASPS from insomnia disorder (where sleep is poor regardless of timing),
    from depression with early-morning waking (where sleep is typically
    nonrestorative), and from familial natural short sleep (where duration
    itself is reduced). Sleep loss in ASPS is secondary to schedule conflict,
    not intrinsic.
  notes: >-
    Deliberately curated WITHOUT a phenotype_term. This assertion is the
    ABSENCE of a sleep-quality abnormality, so binding any HPO abnormality term
    (e.g. HP:0006979 Sleep-wake cycle disturbance) would make the entry assert
    the negation of its own claim and would be read by downstream consumers as
    a positive abnormality. HPO has no "normal sleep architecture" term; a
    normality/negation construct or a new term request would be needed. The
    same discriminating information is carried in the Insomnia Disorder and
    Major Depressive Disorder differential_diagnoses and in the ICSD-3
    criteria set.
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unlike other sleep maintenance disorders, early morning awakenings occur
      after a normal period of undisturbed sleep, that is, the sleep cycle is
      normal for the age.
    explanation: >-
      Directly evidences the discriminating feature - the early awakening
      follows a NORMAL, undisturbed sleep period, explicitly contrasted with
      other sleep-maintenance disorders. This is the sentence that separates
      ASWPD from insomnia disorder.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the patient is allowed to sleep according to his wishes, the PSG
      results show a normal sleep structure.
    explanation: >-
      Objective polysomnographic confirmation that sleep architecture is normal
      when the patient sleeps on their own advanced schedule - the strongest
      form of this claim.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, unlike excessive sleepiness due to other reasons, the
      daytime work or learning ability of people with this disorder is not
      affected by sleepiness.
    explanation: >-
      Distinguishes ASWPD from primary hypersomnias - daytime function is
      preserved, consistent with normal sleep quantity and quality.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe three kindreds with a profound phase advance of the
      sleep-wake, melatonin and temperature rhythms associated with a very
      short tau.
    explanation: >-
      Establishes that the abnormality in the original kindreds is a phase
      advance of otherwise intact sleep-wake, melatonin and temperature
      rhythms, i.e. a timing rather than a sleep-integrity defect. Supports the
      claim only partially, since the abstract does not itself quantify
      preserved sleep architecture.
- name: Sleep Restriction and Functional Impairment
  category: Behavioral
  description: >-
    When the individual resists the advanced schedule at both ends - staying up
    for evening obligations while still waking spontaneously in the early
    morning - the result is chronic curtailment of sleep, with consequent
    daytime dysfunction and social, occupational, and educational impairment.
    This, rather than the phase advance itself, is the source of clinical
    morbidity and the basis for diagnosing a disorder.
  phenotype_term:
    preferred_term: Sleep deprivation
    term:
      id: HP:0002360
      label: Sleep disturbance
    temporality: CHRONIC
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The main clinical manifestations are insomnia and excessive daytime
      sleepiness that often lead to clinically meaningful distress or cause
      mental, physical, social, occupational, educational, or other functional
      impairment.
    explanation: >-
      Documents the functional-impairment domains that result from circadian
      sleep-wake disorders.
- name: Advanced Melatonin Secretion Phase
  category: Laboratory
  description: >-
    The objective biomarker of the disorder - the nocturnal rise in pineal
    melatonin secretion, and hence dim light melatonin onset (DLMO), occurs
    several hours earlier than normal. In the original FASPS kindreds the
    melatonin rhythm was advanced by approximately 4 hours in parallel with the
    sleep and temperature rhythms. The abnormality is one of timing, not of
    melatonin amount.
  phenotype_term:
    preferred_term: Advanced phase of melatonin secretion
    term:
      id: HP:0012689
      label: Abnormal pineal melatonin secretion
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals are "morning larks" with a 4-hour advance of the
      sleep, temperature, and melatonin rhythms
    explanation: >-
      Quantifies the advance of the melatonin rhythm specifically, which is
      what DLMO measurement detects.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe three kindreds with a profound phase advance of the
      sleep-wake, melatonin and temperature rhythms associated with a very
      short tau.
    explanation: >-
      Independently documents the profound phase advance of the melatonin
      rhythm in the original kindreds.
  notes: >-
    HP:0012689 is defined as "An anomaly in the amount or timing of melatonin
    secretion by the pineal gland", so the timing sense is within its scope;
    the more specific claim (advance rather than delay) is carried by
    preferred_term and description, as HPO has no direction-specific child.
environmental:
- name: Morning and Early-Day Light Exposure
  description: >-
    Light is the dominant zeitgeber, and its effect is direction-dependent via
    the phase-response curve. Disproportionate light exposure in the early
    morning - the phase-advance portion of the curve - reinforces and stabilizes
    an already-advanced clock. This is the environmental counterpart of the
    disorder's mechanism and the reason morning bright light is contraindicated
    in ASPS even though it is therapeutic in delayed sleep-wake phase disorder.
  effect: EXACERBATES
  evidence:
  - reference: PMID:21243069
    reference_title: "Therapeutics for Circadian Rhythm Sleep Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Light is the strongest entraining agent of circadian rhythms and timed
      exposure to bright light is often used in the treatment of circadian
      rhythm sleep disorders.
    explanation: >-
      Establishes light as the strongest entraining agent, whose timing
      determines the direction of the resulting phase shift.
- name: Insufficient Evening Light Exposure
  description: >-
    The converse exposure. Inadequate light in the evening removes the natural
    phase-delaying input that would otherwise oppose an advanced clock,
    allowing the advance to persist. Reduced evening activity and early
    retirement to a dark bedroom compound this, which is one reason the
    phenotype becomes more prominent after retirement and in institutionalized
    older adults.
  effect: EXACERBATES
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If an individual receives less light in the afternoon or evening, or is
      prematurely exposed to morning light following early awakening, the
      circadian rhythm can be advanced, leading to an increased risk of an
      early sleep phase
    explanation: >-
      Directly evidences both halves of the behavioral/environmental
      contribution - insufficient afternoon/evening light AND premature morning
      light exposure - as advancing the circadian rhythm and raising the risk of
      an early sleep phase. Note this also describes a self-reinforcing loop:
      early awakening leads to earlier light exposure, which further advances
      the clock.
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Age-related alterations in circadian rhythms are exacerbated and
      compounded by neurodegenerative disorders, impacting the suprachiasmatic
      nucleus (SCN), sensitivity to light, and light responsiveness in those
      affected.
    explanation: >-
      Adds the age-related dimension - impaired light sensitivity and
      responsiveness. Marked PARTIAL because it addresses reduced light
      responsiveness rather than reduced evening light exposure specifically.
- name: Rigid Conventional Social and Occupational Schedule
  description: >-
    A non-photic environmental determinant of whether an advanced chronotype
    becomes a disorder. An early clock is only impairing when the person is
    required to be awake and functional in the evening or asleep past their
    spontaneous wake time. Schedules that permit early sleep and early rising
    render the same biology asymptomatic - which is also why ASPS is
    under-ascertained.
  effect: EXACERBATES
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Advanced sleep phase (ASP) is seldom brought to medical attention because
      many individuals easily adapt to their early chronotype
    explanation: >-
      Supports that adaptability of the schedule determines whether the
      phenotype presents clinically at all.
clinical_trials:
- name: NCT00246454
  status: COMPLETED
  description: >-
    Completed observational study (Northwestern University) of circadian
    rhythms and sleep propensity in familial advanced and familial delayed
    sleep phase syndrome. The largest ASPS-specific human cohort in this
    evidence set; ASPS inclusion required morning-type preference and an
    advanced melatonin onset.
  evidence:
  - reference: clinicaltrials:NCT00246454
    supports: SUPPORT
    snippet: >-
      The purpose of this study is to determine the properties of circadian
      rhythms and sleep propensity in familial advanced and delayed sleep phase
      syndrome (DSPS).
    explanation: >-
      Directly establishes an ASPS-specific observational cohort characterizing
      circadian rhythms and sleep propensity in the familial form.
- name: NCT04690504
  status: COMPLETED
  description: >-
    Completed biomarker-validation study (Brigham and Women's Hospital)
    comparing single-sample plasma-proteomic and monocyte-transcript estimates
    of circadian phase against melatonin phase in patients with circadian
    rhythm sleep disorders. Relevant to ASPS because the practical barrier to
    diagnosis and to correctly timed light therapy is the burden of serial
    DLMO sampling.
  evidence:
  - reference: clinicaltrials:NCT04690504
    supports: SUPPORT
    snippet: >-
      The investigators aim to develop a method that can estimate individual
      circadian time with a single blood sample taken at any time of the day or
      night.
    explanation: >-
      Establishes the aim of replacing burdensome serial circadian phase
      sampling with a single-sample estimate, the key translational bottleneck
      for circadian rhythm sleep disorders including ASPS.
genetic:
- name: PER2
  notes: >-
    The original FASPS gene. The p.Ser662Gly (S662G) missense variant lies in
    the CK1epsilon-binding region and removes a CK1 phosphoacceptor serine,
    causing PER2 hypophosphorylation. Autosomal dominant with high penetrance
    in the index kindred. Linkage localized the trait to the telomeric region
    of chromosome 2q.
  gene_term:
    preferred_term: PER2
    term:
      id: hgnc:8846
      label: PER2
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:11232563
    reference_title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report localization of the FASPS gene near the telomere of
      chromosome 2q. A strong candidate gene (hPer2), a human homolog of the
      period gene in Drosophila, maps to the same locus.
    explanation: >-
      Establishes PER2 as the FASPS gene by positional mapping to 2qter.
- name: CSNK1D
  notes: >-
    Encodes casein kinase I delta, the kinase that phosphorylates PER2. The
    p.Thr44Ala (T44A) missense variant reduces kinase activity and causes
    FASPS, phenocopying the PER2 substrate mutation.
  gene_term:
    preferred_term: CSNK1D
    term:
      id: hgnc:2452
      label: CSNK1D
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:15800623
    reference_title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the identification of a missense mutation (T44A) in the
      human CKIdelta gene, which results in FASPS.
    explanation: Establishes CSNK1D T44A as causative for FASPS.
- name: CRY2
  notes: >-
    Encodes cryptochrome 2, a negative-limb repressor. The p.Ala260Thr (A260T)
    variant in the FAD-binding domain phosphate loop increases FBXL3-mediated
    degradation of CRY2 and co-segregated with FASP in one family.
  gene_term:
    preferred_term: CRY2
    term:
      id: hgnc:2385
      label: CRY2
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:27529127
    reference_title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene
      that co-segregates with FASP in one family.
    explanation: >-
      Establishes CRY2 A260T co-segregation with FASP. Note the evidence base
      is a single family.
- name: TIMELESS
  notes: >-
    Encodes the mammalian TIMELESS protein. A reported mutation prevents
    nuclear TIM accumulation and alters CRY2 affinity, causing FASP
    predominantly via altered photic entrainment rather than period shortening.
    Evidence rests on one small family plus a CRISPR mouse model.
  gene_term:
    preferred_term: TIMELESS
    term:
      id: hgnc:11813
      label: TIMELESS
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a mutation in the human TIMELESS (hTIM) gene that causes
      familial advanced sleep phase (FASP).
    explanation: Establishes TIMELESS as a FASP gene.
- name: PER3
  notes: >-
    Encodes period circadian regulator 3. The P415A/H417R variant haplotype was
    reported in familial advanced sleep phase co-occurring with a seasonal mood
    trait; the variants destabilize PER3 and fail to stabilize PER1/PER2. The
    evidence is weaker than for PER2/CSNK1D - a single kindred with a
    two-variant haplotype and a compound phenotype - so PER3 is curated here as
    a contributory rather than definitively established ASPS gene.
  gene_term:
    preferred_term: PER3
    term:
      id: hgnc:8847
      label: PER3
  relationship_type: DISPUTED
  evidence:
  - reference: PMID:26903630
    reference_title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two rare variants in the circadian clock gene PERIOD3
      (PER3-P415A/H417R) in humans with familial advanced sleep phase
      accompanied by higher Beck Depression Inventory and seasonality scores.
    explanation: >-
      Supports a PER3 contribution but only partially, because the reported
      phenotype bundles advanced sleep phase with a mood/seasonality trait and
      derives from a single kindred.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Familial ASPS segregates as an autosomal dominant trait with high
    penetrance. Penetrance across genes and families beyond the original
    kindreds is not well quantified and may be modified by age and light
    environment.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The trait segregates as an autosomal dominant with high penetrance.
    explanation: >-
      Directly establishes autosomal dominant inheritance with high penetrance.
definitions:
- name: Advanced Sleep-Wake Phase Disorder Diagnostic Criteria (ICSD-3-aligned)
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Consensus clinical criteria for advanced sleep-wake phase disorder. The
    defining requirements are (a) a stable advance of the major sleep episode
    relative to the desired or required sleep and wake times, (b) symptoms -
    evening sleepiness and/or early-morning awakening - present for at least
    three months, (c) improvement in sleep quality and duration when the
    individual is allowed to follow their own preferred early schedule, (d)
    objective corroboration by sleep diary plus actigraphy for at least seven
    and preferably fourteen days including both work and free days, and (e)
    exclusion of another sleep, medical, neurological, psychiatric,
    medication-related, or environmental explanation.
  criteria_sets:
  - name: Core clinical criteria
    description: >-
      Criteria that must be jointly satisfied to diagnose ASWPD rather than a
      non-disordered advanced chronotype.
    core_clinical_characteristics:
    - preferred_term: Advance of the major sleep episode relative to desired sleep-wake time
      term:
        id: HP:0031873
        label: Early chronotype
    - preferred_term: Evening sleepiness
      term:
        id: HP:0002329
        label: Drowsiness
    - preferred_term: Early-morning awakening with inability to return to sleep
      term:
        id: HP:0031356
        label: Terminal insomnia
    additional_requirements:
    - preferred_term: >-
        Sleep onset and wake times occur at least 2 hours earlier than the
        societal norm
    - preferred_term: Symptoms present for at least three months
    - preferred_term: >-
        Sleep quality and duration improve when following the self-selected
        early schedule
    - preferred_term: >-
        Sleep diary plus actigraphy for at least 7 (preferably 14) days,
        including work and free days
    exclusion_criteria:
    - preferred_term: >-
        Another sleep, medical, neurological, psychiatric, medication-related,
        or environmental explanation for the sleep timing
    evidence:
    - reference: PMID:34493186
      reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The main clinical manifestations are insomnia and excessive daytime
        sleepiness that often lead to clinically meaningful distress or cause
        mental, physical, social, occupational, educational, or other
        functional impairment.
      explanation: >-
        Supports the requirement that symptoms produce clinically meaningful
        distress or functional impairment, which is what distinguishes the
        disorder from a well-tolerated advanced chronotype.
    - reference: PMID:39864932
      reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Advanced sleep-wake phase disorder (ASWPD) is characterized by a
        consistent and distressing anticipation of sleep-wake timing
      explanation: >-
        Supports the core criterion of a consistent (stable) and distressing
        advance of sleep-wake timing.
    - reference: PMID:34493186
      reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        2) symptoms are present for at least 3 months; 3) when patients are
        allowed to sleep in accordance with their internal biological clock,
        sleep quality and duration are improved with a consistent but advanced
        timing of the major sleep episode; 4) sleep logs and, whenever
        possible, actigraphy monitoring for at least 7 days (preferably 14
        days), including work/school days and free days, demonstrate a stable
        advance in the timing of the habitual sleep period; and 5) the sleep
        disturbance is not better explained by another current sleep disorder,
        medical or neurologic disorder, mental disorder, medication use, or
        substance use disorder.
      explanation: >-
        Verbatim statement of ICSD criteria 2-5, directly sourcing the numeric
        thresholds used in this criteria set (3 months; 7-14 days of sleep logs
        plus actigraphy) as well as the improvement-on-preferred-schedule
        requirement and the exclusion criterion.
    - reference: PMID:34493186
      reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        sleep onset and wake times usually occur at least 2 hours earlier than
        the societal norm compared with normal individuals
      explanation: >-
        Sources the >=2 hour advance threshold that quantifies criterion 1.
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sleep diaries, actigraphy, and determination of day and night phase
      markers (dim light melatonin onset and core body temperature minimum)
      have all become routine diagnostic methods for CRSWDs.
    explanation: >-
      Establishes the routine objective diagnostic measures required by the
      criteria set.
  notes: >-
    The distress/impairment requirement is what separates ASWPD (a disorder)
    from an extreme but well-tolerated advanced chronotype. Many people with a
    markedly advanced phase never meet criteria because they arrange their
    lives around it.

    PROVENANCE: every numeric threshold in this criteria set is now sourced to
    a verbatim quotation. PMID:34493186 restates the five ICSD criteria in full
    ("The diagnosis of ASWPD requires that the following five main criteria are
    met") and separately gives the >=2 hour advance threshold. The definition is
    named "ICSD-3-aligned" because the criteria are quoted from a review
    restating them rather than from the ICSD-3 manual itself, which is not
    PubMed-indexed and therefore not citable under the project's snippet rules.
- name: Dim Light Melatonin Onset (DLMO) Phase Assessment
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The reference measurement protocol for objectively locating circadian
    phase. Serial salivary or plasma melatonin samples are collected under
    dim-light conditions over several hours before habitual bedtime, and DLMO
    is the clock time at which melatonin rises above a defined assay threshold.
    In ASPS, DLMO occurs abnormally early. Core body temperature minimum is an
    equivalent phase marker. DLMO is what converts a patient report of early
    sleep into a demonstrated circadian phase advance, and it is what allows
    light therapy to be timed on the correct side of the phase-response curve -
    which is why it is a treatment-enabling measurement, not merely a
    confirmatory one.
  notes: >-
    Typed as OTHER rather than PHENOTYPE_ALGORITHM: this is a laboratory
    phase-assessment protocol, not a computable EHR/OMOP case-finding query,
    which is what PHENOTYPE_ALGORITHM denotes in this schema. No
    `validation_status` is asserted, because DLMO IS the reference standard for
    circadian phase - it is the comparator against which candidate biomarkers
    are validated, so it cannot coherently be marked
    VALIDATED_AGAINST_GOLD_STANDARD against itself. A specific numeric
    salivary-melatonin threshold is deliberately not stated here; thresholds
    are assay- and laboratory-dependent and no cached source states one
    verbatim. See also the parallel `diagnosis` entry, which records DLMO as a
    diagnostic test; this entry records the measurement definition.
  evidence:
  - reference: clinicaltrials:NCT04690504
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      circadian phase estimates from the biomarker panels will be compared with
      those derived from plasma or saliva melatonin (the current "gold-standard"
      circadian phase marker)
    explanation: >-
      Establishes plasma/saliva melatonin phase as the current gold-standard
      circadian phase marker - the reason no separate validation status is
      asserted for DLMO itself.
  - reference: clinicaltrials:NCT04690504
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current methods for assessing circadian timing require sampling over
      hours (or even up to a day) while the patient is in controlled
      conditions.
    explanation: >-
      Documents the serial-sampling-under-controlled-conditions burden that
      defines the DLMO protocol and motivates ongoing biomarker development.
  - reference: PMID:10470086
    reference_title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe three kindreds with a profound phase advance of the
      sleep-wake, melatonin and temperature rhythms associated with a very
      short tau.
    explanation: >-
      Demonstrates that the melatonin and temperature phase markers are
      advanced in ASPS, which is what DLMO assessment detects.
diagnosis:
- name: Sleep diary and actigraphy
  description: >-
    Concurrent sleep diary and wrist actigraphy for at least seven (preferably
    fourteen) consecutive days, spanning both work and free days, to document
    that the advance of sleep timing is stable and habitual rather than
    situational.
  diagnosis_term:
    preferred_term: actigraphy
    term:
      id: NCIT:C180883
      label: Actigraphy
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sleep diaries, actigraphy, and determination of day and night phase
      markers (dim light melatonin onset and core body temperature minimum)
      have all become routine diagnostic methods for CRSWDs.
    explanation: >-
      Establishes sleep diaries and actigraphy as routine diagnostic methods
      for circadian rhythm sleep-wake disorders.
- name: Dim light melatonin onset (DLMO)
  description: >-
    Serial melatonin sampling under dim light to establish that the endogenous
    circadian phase - not merely the behavioral schedule - is advanced. Also
    required to time light therapy correctly relative to the phase-response
    curve.
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      determination of day and night phase markers (dim light melatonin onset
      and core body temperature minimum) have all become routine diagnostic
      methods for CRSWDs
    explanation: >-
      Establishes DLMO as a routine circadian phase marker in the diagnostic
      workup.
- name: Circadian clock gene panel or exome/genome sequencing
  description: >-
    Molecular testing is appropriate for a strongly familial, extreme,
    early-onset phenotype, and should cover the five reported ASPS genes -
    PER2, CSNK1D, CRY2, PER3, and TIMELESS. Sequence analysis (panel or
    exome/genome) is the relevant modality; karyotype, chromosomal microarray,
    mitochondrial sequencing, and repeat-expansion testing have no routine
    indication. Interpretation must be cautious: segregation, population
    frequency, functional data, and ACMG/AMP classification are all required,
    because several of these gene-disease relationships rest on single
    kindreds. Cascade testing is reasonable only once a pathogenic or likely
    pathogenic familial variant is established, and predictive testing of
    asymptomatic minors warrants counselling because an early chronotype may
    never cause disorder-level impairment.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal dominant mutations in circadian clock genes like PER2, CK1,
      PER3, CRY2, TIMELESS, and DEC2 have been linked to FASP
    explanation: >-
      Establishes the gene set that a circadian-clock panel should cover in
      suspected familial advanced sleep phase.
- name: Polysomnography to exclude comorbid sleep disorders
  description: >-
    Polysomnography is not required to diagnose ASPS and does not itself
    demonstrate circadian phase. It is used to exclude comorbid conditions -
    most importantly obstructive sleep apnea, which is frequently the reason an
    individual with unrecognized advanced sleep phase presents to a sleep
    clinic in the first place.
  diagnosis_term:
    preferred_term: polysomnography
    term:
      id: NCIT:C114185
      label: Polysomnography
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      is mostly discovered coincidentally in the presence of other sleep
      disorders, mainly obstructive sleep apnea syndrome (OSAS)
    explanation: >-
      Supports the role of a sleep-disorder workup, since FASP is typically
      discovered incidentally during evaluation for obstructive sleep apnea.
differential_diagnoses:
- name: Delayed Sleep-Wake Phase Disorder
  description: >-
    The mirror-image intrinsic circadian rhythm sleep-wake disorder, and by far
    the more commonly diagnosed of the two. Both are disorders of sleep timing
    with normal sleep when the preferred schedule is followed, and they share
    almost all of their clinical vocabulary - which is precisely why the
    literatures are easy to conflate. The direction of the phase shift is
    opposite and so is the treatment: DSWPD is treated with morning light and
    evening melatonin to advance the clock, ASPS with evening light to delay
    it. Applying DSWPD treatment to ASPS would worsen it.
  disease_term:
    preferred_term: circadian rhythm sleep disorder, delayed sleep phase type
    term:
      id: MONDO:0024377
      label: circadian rhythm sleep disorder, delayed sleep phase type
  distinguishing_features:
  - Sleep onset and offset are late (typically 02:00-06:00 onset) rather than early
  - Presenting complaint is sleep-onset insomnia and difficulty awakening in the morning, rather than evening sleepiness and early-morning awakening
  - Dim light melatonin onset (DLMO) is late rather than early
  - Onset is predominantly in adolescence rather than in early adulthood or with aging
  - Treatment direction is opposite - morning light and evening melatonin, versus evening light for ASPS
  evidence:
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      strategically timed melatonin (for the treatment of DSWPD, blind adults
      with N24SWD, and children/ adolescents with ISWRD and comorbid
      neurological disorders), and light therapy with or without accompanying
      behavioral interventions (adults with ASWPD, children/adolescents with
      DSWPD, and elderly with dementia)
    explanation: >-
      Shows that AASM issues DIFFERENT treatment recommendations for ASWPD
      (light therapy) and DSWPD (melatonin, plus light therapy only in
      children/adolescents) - concrete evidence that the two disorders are
      distinct and are not managed interchangeably.
- name: Non-24-Hour Sleep-Wake Rhythm Disorder
  description: >-
    A circadian disorder in which the clock fails to entrain to the 24-hour day
    at all, so sleep timing drifts progressively later (or, rarely, earlier)
    day after day. Most common in totally blind individuals lacking photic
    input.
  disease_term:
    preferred_term: non-24-hour sleep-wake syndrome
    term:
      id: MONDO:0019137
      label: non-24-hour sleep-wake syndrome
  distinguishing_features:
  - Sleep timing progressively drifts rather than being stably advanced
  - Symptoms cycle between asymptomatic and symptomatic periods as the endogenous rhythm moves in and out of alignment
  - Actigraphy over several weeks shows a characteristic staircase pattern rather than a fixed early schedule
  - Strongly associated with total blindness and absent photic input
  evidence:
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      strategically timed melatonin (for the treatment of DSWPD, blind adults
      with N24SWD, and children/ adolescents with ISWRD and comorbid
      neurological disorders)
    explanation: >-
      Confirms N24SWD as a separate intrinsic circadian disorder with its own
      (melatonin-based, blindness-associated) treatment recommendation,
      distinct from ASWPD.
- name: Major Depressive Disorder with Early-Morning Awakening
  description: >-
    A clinically important differential in the opposite direction - terminal
    insomnia is a classic melancholic feature of major depression, and an ASPS
    patient reporting that they always wake at 4 a.m. is readily misread as
    depressed. Conversely, a depressed patient may be misclassified as having a
    circadian disorder. Getting this wrong matters because the treatments
    diverge completely, and because PER3-associated FASP is itself reported
    alongside elevated depression and seasonality scores, so the two can
    genuinely co-occur.
  disease_term:
    preferred_term: major depressive disorder
    term:
      id: MONDO:0002009
      label: major depressive disorder
  distinguishing_features:
  - Evening sleepiness is absent in depression; sleep onset is often delayed or unimpaired rather than involuntarily early
  - Sleep is nonrestorative in depression, whereas in ASPS it is restorative when taken at the preferred early hours
  - The whole circadian ensemble need not be phase-advanced in depression; DLMO is typically normal
  - Core depressive symptoms (anhedonia, low mood, guilt, appetite and psychomotor change) are present in depression and typically absent in ASPS
  evidence:
  - reference: PMID:26903630
    reference_title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two rare variants in the circadian clock gene PERIOD3
      (PER3-P415A/H417R) in humans with familial advanced sleep phase
      accompanied by higher Beck Depression Inventory and seasonality scores.
    explanation: >-
      Documents genuine co-occurrence of familial advanced sleep phase with
      depression scores, showing why the depression differential is both
      important and not always exclusive.
- name: Insomnia Disorder
  description: >-
    Chronic insomnia is the most frequent misdiagnosis in ASPS, because the
    early-morning awakening is reported as terminal insomnia. This
    misclassification commonly leads to hypnotic prescription, which suppresses
    the symptom without correcting circadian phase and carries particular risk
    (falls, confusion, next-day impairment) in the older adults in whom
    advanced phase is most prevalent.
  disease_term:
    preferred_term: insomnia
    term:
      id: MONDO:0013600
      label: insomnia
  distinguishing_features:
  - In insomnia disorder sleep is poor regardless of when it is attempted; in ASPS sleep is normal once permitted at the advanced biological time
  - Sleep-onset latency is prolonged even at the preferred bedtime in insomnia disorder, but short in ASPS
  - A sleep diary showing consistently early, consolidated, restorative sleep on free days discriminates the two
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CRSWDs are easily mistaken for insomnia or early waking up, resulting in
      inappropriate treatment.
    explanation: >-
      Directly documents that circadian rhythm sleep-wake disorders are
      commonly misdiagnosed as insomnia, with inappropriate treatment as the
      consequence.
- name: Irregular Sleep-Wake Rhythm Disorder
  description: >-
    Particularly relevant to the sporadic/age-related arm, since it arises in
    the same population - older adults, and especially those with dementia, in
    whom SCN degeneration is advanced. Whereas ASPS represents a coherent
    circadian rhythm shifted early, ISWRD represents loss of a consolidated
    rhythm altogether, with sleep fragmented into multiple bouts across the 24
    hours. Sundowning and fragmented nocturnal sleep in dementia typically
    belong here rather than to ASPS.
  disease_term:
    preferred_term: circadian rhythm sleep disorder, irregular sleep wake type
    term:
      id: MONDO:0024379
      label: circadian rhythm sleep disorder, irregular sleep wake type
  distinguishing_features:
  - At least three irregular sleep episodes per 24-hour period, rather than one consolidated but early sleep episode
  - No stable phase relationship to clock time, so actigraphy shows fragmentation rather than a consistent early schedule
  - Total sleep across 24 hours may be normal but is not consolidated, whereas ASPS sleep is consolidated and normal in architecture
  - AASM gives it different treatment recommendations from ASWPD (melatonin in children/adolescents with comorbid neurological disorders; light therapy in elderly with dementia)
  evidence:
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recommendations against the use of melatonin and discrete sleep-promoting
      medications are provided for demented elderly patients
    explanation: >-
      Shows ISWRD in demented elderly patients attracts a recommendation
      AGAINST melatonin and hypnotics, the opposite management posture from
      ASWPD - so the distinction is clinically consequential.
- name: Shift Work Disorder
  description: >-
    An extrinsic circadian disorder in which the misalignment is imposed by an
    externally mandated schedule rather than arising from the endogenous clock.
    Included because it is the standard exclusion when a patient reports sleep
    at unconventional hours, and because shift work and transmeridian travel
    were exclusion criteria in the major ASPS observational protocols.
  disease_term:
    preferred_term: circadian rhythm sleep disorder, shift work type
    term:
      id: MONDO:0024382
      label: circadian rhythm sleep disorder, shift work type
  distinguishing_features:
  - Caused by external behavioral/occupational factors rather than an intrinsic clock abnormality
  - Resolves or substantially improves when the imposed schedule is removed, whereas ASPS persists
  - Sleep timing follows the work roster rather than a stable early endogenous phase
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      extrinsic circadian rhythm sleep-wake disorders, in which sleep
      disorders, such as jet lag or shift-work disorder, result from
      environmental changes that cause a mismatch between sleep-wakefulness
      times and internal circadian rhythms
    explanation: >-
      Establishes the extrinsic/intrinsic distinction that separates shift work
      disorder (and jet lag) from ASPS, which is an intrinsic CRSWD.
- name: Obstructive Sleep Apnea Syndrome
  description: >-
    Not a mimic so much as a confounder and frequent companion. Familial
    advanced sleep phase is most often discovered incidentally during
    evaluation for obstructive sleep apnea, and OSA independently causes
    fragmented sleep and daytime sleepiness that can obscure or be attributed
    to the circadian abnormality.
  disease_term:
    preferred_term: obstructive sleep apnea syndrome
    term:
      id: MONDO:0007147
      label: obstructive sleep apnea syndrome
  distinguishing_features:
  - OSA produces snoring, witnessed apneas, and sleep fragmentation with non-restorative sleep at any schedule
  - OSA is confirmed by polysomnography and does not shift circadian phase markers
  - The two frequently coexist, so identifying OSA does not exclude ASPS
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      is mostly discovered coincidentally in the presence of other sleep
      disorders, mainly obstructive sleep apnea syndrome (OSAS)
    explanation: >-
      Establishes OSA as the usual clinical context in which familial advanced
      sleep phase comes to attention.
treatments:
- name: Timed Evening Bright Light Therapy
  description: >-
    The principal evidence-based treatment. Bright light delivered in the
    evening falls on the phase-delay portion of the human phase-response curve
    and pushes the advanced clock later. Phototherapy for ASWPD is usually
    given between 19:00 and 21:00, and the recommended dose to achieve a phase
    delay is at least 5,000 lux for 2 hours at night. The AASM 2015 guideline
    gives light therapy positive endorsement, at a second-tier degree of
    confidence, for adults with ASWPD, and the AASM guideline is summarized in
    the review literature as recommending night bright light therapy for ASWPD
    specifically.

    Tolerability is the main practical limitation: multiple studies report that
    elderly patients exposed to bright light at night could not tolerate it,
    resulting in poor compliance, and one comparison found better compliance
    (and symptom improvement) with dim rather than enhanced-intensity evening
    light. Side effects are otherwise minimal (eye fatigue, nausea,
    restlessness, headache) and usually self-limiting.

    DIRECTION IS CRITICAL. The same intervention mistimed does harm - morning
    bright light falls on the phase-advance portion of the curve and would
    further advance an already-advanced clock, worsening the disorder. Correct
    timing therefore depends on knowing circadian phase (DLMO or core body
    temperature minimum), not merely clock time. Tolerance of prolonged evening
    light can be poor in older adults, the group in whom ASPS is most common.
  treatment_term:
    preferred_term: bright white light therapy
    term:
      id: NCIT:C174524
      label: Bright White Light Therapy
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Altered Photic Entrainment of the Circadian Pacemaker
    treatment_effect: MODULATES
    description: >-
      Evening light exploits the delay portion of the phase-response curve to
      shift the entrained phase later, counteracting the advance.
  evidence:
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      light therapy with or without accompanying behavioral interventions
      (adults with ASWPD, children/adolescents with DSWPD, and elderly with
      dementia)
    explanation: >-
      AASM guideline gives light therapy (with or without behavioral
      interventions) positive second-tier endorsement specifically for adults
      with ASWPD.
  - reference: PMID:21243069
    reference_title: "Therapeutics for Circadian Rhythm Sleep Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Light is the strongest entraining agent of circadian rhythms and timed
      exposure to bright light is often used in the treatment of circadian
      rhythm sleep disorders.
    explanation: >-
      Supports timed bright light as the principal entraining intervention for
      circadian rhythm sleep disorders.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phototherapy is usually performed between 19:00~21:00 hours, which can
      improve sleep efficiency and delay the circadian rhythm
    explanation: >-
      Provides the specific EVENING timing window (19:00-21:00) and confirms
      the intended direction of effect is a circadian DELAY - the direction
      that corrects an advanced phase.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To delay the circadian rhythm time, it is recommended that individuals
      are exposed to at least 5,000 lux of bright light at night for 2 hours
    explanation: >-
      Provides the recommended light dose (>=5,000 lux) and duration (2 hours,
      at night) for achieving the phase delay required in ASWPD.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The latest AASM guideline recommends the use of night bright light
      therapy in the treatment of ASWPD
    explanation: >-
      Independent review-level confirmation that the AASM recommendation for
      ASWPD is specifically for NIGHT (evening) bright light.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiple studies have shown that the circadian rhythm phase is delayed in
      elderly patients exposed to bright light at night; however, these
      patients reported that they could not tolerate light, which resulted in
      poor compliance
    explanation: >-
      Documents both efficacy (phase delay in elderly patients) and the key
      practical limitation (intolerance and poor compliance). Marked PARTIAL
      because it simultaneously supports and qualifies the treatment.
  notes: >-
    Strength of recommendation should not be overstated. The AASM 2015
    recommendation for light therapy in adult ASWPD is graded WEAK FOR on
    VERY LOW quality evidence: the single randomized ASWPD trial identified by
    the AASM systematic review was small (47 participants, mean age 70) and
    used relatively dim evening light (~265 lux), and it did not find a
    significant post-treatment group difference. Reported side effects of
    phototherapy (eye fatigue, nausea, restlessness, headaches) are minimal and
    usually resolve spontaneously.
- name: Strategically Timed Melatonin
  description: >-
    Exogenous melatonin shifts circadian phase according to a phase-response
    curve that is approximately the inverse of the light PRC - melatonin taken
    in the morning delays the clock, whereas melatonin taken in the evening
    advances it. For ASPS the theoretically correct direction is therefore
    MORNING melatonin to produce a phase delay, the exact opposite of the
    evening dosing used in delayed sleep-wake phase disorder. Evening melatonin
    would advance the clock further and is expected to worsen ASPS.

    This treatment is included because review-level literature reports timed
    melatonin as useful across circadian rhythm sleep disorders including
    advanced sleep phase, but it must be flagged that the AASM 2015 guideline
    did NOT endorse melatonin for ASWPD - its melatonin endorsement was
    restricted to DSWPD, blind adults with N24SWD, and children/adolescents
    with ISWRD. Morning dosing also risks residual daytime sleepiness.
    Melatonin for ASPS should therefore be regarded as mechanistically rational
    but not guideline-supported.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: melatonin
      term:
        id: CHEBI:16796
        label: melatonin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
    treatment_effect: MODULATES
    description: >-
      Morning-timed exogenous melatonin acts on the melatonin phase-response
      curve to delay the advanced circadian phase.
  evidence:
  - reference: PMID:21243069
    reference_title: "Therapeutics for Circadian Rhythm Sleep Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, timed administration of melatonin, either alone or in
      combination with light therapy has been shown to be useful in the
      treatment of the following circadian rhythm sleep disorders: delayed
      sleep phase, advanced sleep phase, free-running, irregular sleep wake,
      jet lag and shift work.
    explanation: >-
      Review-level support for timed melatonin, explicitly naming advanced
      sleep phase among the circadian disorders in which it is useful.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      According to the melatonin PRC, to delay the circadian rhythm phase of
      ASWPD, melatonin should be given in the early morning.
    explanation: >-
      Directly evidences the DIRECTION of melatonin dosing for ASWPD - EARLY
      MORNING to produce a phase delay. This is the opposite of the evening
      dosing used in delayed sleep-wake phase disorder, and getting it backwards
      would worsen the disorder.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: >-
      However, there is a lack of clinical data and information regarding the
      safety and effectiveness of melatonin
    explanation: >-
      Records the ABSENCE of clinical safety/efficacy data for melatonin in
      ASWPD. Classified NO_EVIDENCE rather than REFUTE because absence of data
      is not refutation - consistent with how the AASM guideline gap is
      recorded elsewhere in this treatment.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      In addition, melatonin has a sedative and hypnotic effect, so taking
      melatonin in the morning may make it difficult to stay awake, making it
      more difficult for individuals to stick to the scheduled sleep and
      wake-up times
    explanation: >-
      Documents the specific harm of the mechanistically-indicated morning
      dosing - daytime sedation undermining the very schedule the treatment is
      meant to establish. A concrete argument against routine use.
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No recommendations were provided for remaining treatments/ populations,
      due to either insufficient or absent data.
    explanation: >-
      Melatonin for ASWPD falls among the treatment/population combinations for
      which the AASM guideline could make no recommendation, in contrast to its
      positive melatonin endorsement for DSWPD, N24SWD, and ISWRD. Recorded as
      NO_EVIDENCE to keep the guideline gap explicit rather than implying
      endorsement.
- name: Schedule Accommodation and Sleep Scheduling
  description: >-
    Where occupational and social circumstances permit, the simplest and often
    the most effective management is to accommodate the early schedule rather
    than fight it, since sleep is normal when taken at the biologically
    preferred time. Where a delay is required, a prescribed and consistently
    maintained later sleep-wake schedule may be attempted, typically alongside
    evening light. The AASM guideline made no recommendation on prescribed
    sleep scheduling or timed exercise for ASWPD because the evidence was
    insufficient.

    Health education and behavioral guidance for ASWPD explicitly includes
    AVOIDANCE OF BRIGHT LIGHT IN THE MORNING - the direction-critical negative
    instruction, since morning light sits on the phase-advance limb of the PRC
    and would worsen the disorder - alongside a midday nap, postponing bedtime,
    physical activity, and walking outdoors in the evening under bright light.
    Chronotherapy for ASWPD delays sleep onset progressively (by 3 hours every
    2 days) until the desired later bedtime is reached; a single case
    maintained a 23:00 bedtime at 5-month follow-up.
  treatment_term:
    preferred_term: behavioral and educational intervention
    term:
      id: NCIT:C63474
      label: Behavioral, Psychological or Informational Intervention
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Circadian Misalignment with Conventional Social Schedule
    treatment_effect: MODULATES
    description: >-
      Aligning social demands with biological time removes the misalignment
      that generates morbidity, without altering the underlying clock.
  evidence:
  - reference: PMID:26414986
    reference_title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No recommendations were provided for remaining treatments/ populations,
      due to either insufficient or absent data.
    explanation: >-
      Prescribed sleep scheduling and timed exercise for ASWPD are among the
      treatment/population combinations for which the AASM guideline could make
      no recommendation.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Health education and behavioral guidance can be given to patients,
      including the avoidance of bright light in the morning, taking a nap at
      noon, trying to postpone bedtime at night, performing physical
      activities, and walking in the evening under bright light.
    explanation: >-
      Directly evidences the behavioral package for ASWPD, including the
      direction-critical instruction to AVOID morning bright light - the
      negative counterpart of evening light therapy.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the sleep onset time is delayed by 3 hours every 2 days until the sleep
      time is consistent with the desired later bedtime
    explanation: >-
      Gives the chronotherapy schedule specific to ASWPD (progressive DELAY,
      the opposite direction from DSWPD chronotherapy). Marked PARTIAL because
      the supporting clinical evidence is a single case report.
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: >-
      In addition, no study has assessed the use of hypnotic drugs and CBT as
      adjuvant therapy for ASWPD.
    explanation: >-
      Records the explicit evidence gap for hypnotics and CBT in ASWPD -
      relevant because hypnotics are what patients misdiagnosed with insomnia
      commonly receive.
prevalence:
- population: North American sleep clinic patients
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 40.0
  notes: >-
    Advanced sleep-wake phase disorder (ASWPD, i.e. meeting disorder criteria)
    in 2422 consecutive new sleep-clinic patients - at least 0.04%, or about 1
    in 2500. Clinic-based, so not a general-population estimate.
  evidence:
  - reference: PMID:31384946
    reference_title: "Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results demonstrate an ASP prevalence of 0.33%, an FASP prevalence of
      0.21%, and an ASWPD prevalence of at least 0.04%.
    explanation: >-
      Provides the ASWPD prevalence estimate in a sleep clinic population.
- population: North American sleep clinic patients (familial advanced sleep phase)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 210.0
  notes: >-
    Familial advanced sleep phase (FASP) prevalence of 0.21% (about 1 in 475)
    among 2422 new sleep-clinic patients. A 2025 review gives a concordant
    range of 0.21%-0.5%.
  evidence:
  - reference: PMID:31384946
    reference_title: "Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients presenting to a sleep clinic, conservatively 1 out of
      every 300 patients will have ASP, 1 out of every 475 will have FASP, and
      1 out of every 2500 will have ASWPD.
    explanation: >-
      Gives the FASP rate of 1 in 475 (0.21%) in a sleep clinic population.
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The prevalence of FASP is currently estimated to be between 0.21% and
      0.5%.
    explanation: >-
      Independent review-level confirmation of the FASP prevalence range.
- population: Middle-aged adults
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1000.0
  notes: >-
    Review estimate that advanced sleep-wake phase disorder affects almost 1%
    of middle-aged individuals. Substantially higher than the sleep-clinic
    ASWPD figure; reflects differing ascertainment and criteria, and should be
    read as an upper-bound community estimate.
  evidence:
  - reference: PMID:39864932
    reference_title: "Advanced sleep phase syndrome: Role of genetics and aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Advanced sleep-wake phase disorder (ASWPD) is characterized by a
      consistent and distressing anticipation of sleep-wake timing, affecting
      almost 1% of middle-aged individuals.
    explanation: >-
      Provides the community-level ASWPD prevalence estimate in middle-aged
      adults.
notes: >-
  Ascertainment and nomenclature caveats. (1) ASPS is systematically
  under-diagnosed relative to delayed sleep-wake phase disorder. Early rising
  is socially tolerated and often admired, so affected individuals seldom seek
  care; familial cases are typically found incidentally during evaluation for
  another sleep disorder, usually obstructive sleep apnea. The prevalence
  figures above are correspondingly likely to be underestimates of the
  underlying phenotype, though not necessarily of the impairing disorder.
  (2) Three overlapping entities are frequently conflated in the literature and
  should be kept distinct - advanced sleep phase (ASP, an extreme morning
  chronotype), familial advanced sleep phase (FASP, the heritable form), and
  advanced sleep-wake phase disorder (ASWPD, the subset causing distress or
  functional impairment). Only the last is a disorder by ICSD criteria.
  (3) The MONDO concept MONDO:0015609 is classified as a hereditary disease and
  carries FASPS synonyms, so it maps most precisely onto the familial subtype;
  the sporadic/age-related subtype is curated here for clinical completeness
  and differential-diagnostic value.
  (4) No `biochemical:` section is curated. The reference circadian biomarker
  (dim light melatonin onset) is instead carried by the
  `Advanced Melatonin Secretion Phase` phenotype (HP:0012689, whose definition
  covers timing as well as amount), by the `diagnosis` DLMO entry, and by the
  DLMO `definitions` entry. A `biochemical:` entry would require an NCIT
  biomarker term for melatonin measurement reachable from NCIT:C16342; no such
  term was verified, and rather than bind a plausible-but-unchecked identifier
  the section is deliberately deferred. The sibling entry
  Delayed_Sleep_Phase_Syndrome likewise has no `biochemical:` section.
  (5) Obstructive sleep apnea is curated under `differential_diagnoses` as a
  confounder/companion rather than as a comorbidity, because `comorbidities` is
  not a slot on the Disease class in this schema - comorbidity pairs are
  modelled as separate entities under `kb/comorbidities/`. An
  ASPS-OSA comorbidity entry would be a reasonable follow-up.
  (6) DEC2 (BHLHE41) is named alongside the FASP genes in review literature,
  but its best-established human phenotype is familial natural short sleep -
  short sleep duration - rather than phase advance. It is deliberately excluded
  from the genetic section here, since ASPS is defined by normal sleep duration
  at an advanced phase.
discussions:
- discussion_id: asps_per3_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is PER3 a genuine advanced-sleep-phase gene, or is the reported
    P415A/H417R association confounded by the co-reported seasonal mood trait?
  attaches_to:
  - pathophysiology#PER3 Destabilization
  rationale: >-
    The PER3 association rests on a single kindred carrying a two-variant
    haplotype, and the reported human phenotype bundles familial advanced sleep
    phase with elevated Beck Depression Inventory and seasonality scores rather
    than isolated phase advance. The functional data (destabilized PER3,
    failure to stabilize PER1/PER2) are real but do not by themselves establish
    that phase advance, rather than the mood/seasonality trait, is the
    PER3-attributable phenotype. This entry therefore types PER3 as DISPUTED
    rather than CAUSATIVE. No ClinGen gene-disease validity classification
    exists for any ASPS gene.
  proposed_experiments:
  - experiment_id: asps_exp_per3_replication
    name: Independent kindred replication for PER3
    description: >-
      Identify additional unrelated kindreds segregating PER3 variants with
      advanced sleep phase, ideally separating the two variants of the
      P415A/H417R haplotype to determine which (if either) drives the
      circadian phenotype.
  - experiment_id: asps_exp_per3_phase_vs_mood
    name: Phase-versus-mood phenotype separation in PER3 carriers
    description: >-
      Phenotype PER3 variant carriers with DLMO and actigraphy alongside
      structured mood and seasonality assessment, to determine whether phase
      advance occurs independently of the mood trait.
  evidence:
  - reference: PMID:26903630
    reference_title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two rare variants in the circadian clock gene PERIOD3
      (PER3-P415A/H417R) in humans with familial advanced sleep phase
      accompanied by higher Beck Depression Inventory and seasonality scores.
    explanation: >-
      Documents the confounded phenotype - advanced sleep phase reported
      together with a mood/seasonality trait - that motivates this gap.
- discussion_id: asps_melatonin_evidence_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does correctly timed morning melatonin actually produce clinically
    meaningful phase delay in ASWPD without unacceptable daytime sedation?
  attaches_to:
  - pathophysiology#Advanced Circadian Phase of Melatonin, Temperature and Sleep Propensity
  rationale: >-
    Morning melatonin is mechanistically indicated for ASWPD by the melatonin
    phase-response curve, and review literature names advanced sleep phase
    among the disorders in which timed melatonin is useful. But the AASM
    guideline could make no recommendation for melatonin in ASWPD, the review
    literature states outright that clinical safety and effectiveness data are
    lacking, and the sedative effect of morning dosing may undermine the very
    schedule the treatment is meant to establish. The evidence for this
    treatment therefore carries a deliberate mixture of SUPPORT, NO_EVIDENCE,
    and REFUTE items in this entry - an honest reflection of an unresolved
    question rather than an internal inconsistency.
  proposed_experiments:
  - experiment_id: asps_exp_melatonin_rct
    name: Randomized trial of DLMO-timed morning melatonin in ASWPD
    description: >-
      Randomized placebo-controlled trial of morning melatonin timed against
      individually measured DLMO, in DLMO-confirmed ASWPD, with DLMO shift and
      actigraphic sleep timing as primary endpoints and next-day sleepiness
      plus schedule adherence as co-primary safety endpoints, since sedation is
      the predicted failure mode.
  evidence:
  - reference: PMID:34493186
    reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, there is a lack of clinical data and information regarding the
      safety and effectiveness of melatonin
    explanation: States the evidence gap directly.
- discussion_id: asps_variant_and_penetrance_reporting
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the specific TIMELESS variant causing familial advanced sleep
    phase, and what is the penetrance of each ASPS gene?
  attaches_to:
  - pathophysiology#TIMELESS Nuclear Exclusion
  rationale: >-
    The cached TIMELESS abstract establishes that a human TIMELESS mutation
    causes FASP and characterizes its molecular consequences, but names no
    specific variant, so this entry deliberately declines to assert one rather
    than importing an unverifiable variant name from the deep-research report.
    More broadly, penetrance is quantified for none of the five ASPS genes
    beyond the original PER2 kindreds being described as highly penetrant, and
    penetrance may be age- and light-environment-dependent. This limits both
    variant interpretation and genetic counselling.
  proposed_experiments:
  - experiment_id: asps_exp_timeless_variant_sourcing
    name: Source the TIMELESS variant to a citable record
    description: >-
      Extract the specific TIMELESS variant with HGVS nomenclature against a
      stated transcript from the primary full text and ClinVar, so it can be
      asserted with a verifiable citation.
  - experiment_id: asps_exp_penetrance
    name: Age-stratified penetrance estimation across ASPS genes
    description: >-
      Aggregate reported kindreds per gene to estimate age-specific penetrance,
      recording light environment and habitual schedule as covariates given
      that both are expected to modify expression.
  evidence:
  - reference: PMID:31138685
    reference_title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a mutation in the human TIMELESS (hTIM) gene that causes
      familial advanced sleep phase (FASP).
    explanation: >-
      Establishes the gene-disease claim while naming no variant - the gap this
      discussion records.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:34493186
      reference_title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Circadian rhythm sleep-wake disorders (CRSWDs) are a distinct class of
        sleep disorders caused by alterations to the circadian time-keeping
        system, its entrainment mechanisms, or a mismatch between the
        endogenous circadian rhythm and the external environment.
      explanation: >-
        Supports classification as a nervous-system proxy in the current
        schema, which lacks a dedicated sleep/circadian Harrison chapter. Kept
        consistent with the sibling entry Delayed_Sleep_Phase_Syndrome, which
        uses the same NEUROLOGIC assignment and the same rationale.
references:
- reference: PMID:10470086
  title: "Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans."
- reference: PMID:11232563
  title: "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."
- reference: PMID:15800623
  title: "Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome."
- reference: PMID:17218255
  title: "Modeling of a human circadian mutation yields insights into clock regulation by PER2."
- reference: PMID:27529127
  title: "A Cryptochrome 2 mutation yields advanced sleep phase in humans."
- reference: PMID:31138685
  title: "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase."
- reference: PMID:26903630
  title: "A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait."
- reference: PMID:31384946
  title: "Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population."
- reference: PMID:26414986
  title: "Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline."
- reference: PMID:39864932
  title: "Advanced sleep phase syndrome: Role of genetics and aging."
- reference: PMID:34493186
  title: "Treatment of Circadian Rhythm Sleep-Wake Disorders."
- reference: PMID:21243069
  title: "Therapeutics for Circadian Rhythm Sleep Disorders."
- reference: PMID:31400754
  title: "Genetics of the human circadian clock and sleep homeostat."

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References & Deep Research