DiagnosisClinical DiagnosisThe clinical diagnostic features of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) include the following:Clusters of seizures with a frontal semiology*Occurrence of seizures predominantly during sleep*Normal clinical neurologic examinationPreserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occurNormal findings on neuroimaging Ictal EEG that may be normal or obscured by movement artifactInterictal EEG that shows infrequent epileptiform dischargesPresence of the same disorder in other family members with evidence of an autosomal dominant mode of inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004]* History of clusters of brief (5 seconds to 5 minutes) nocturnal motor seizures which are often stereotyped and may include nightmares, verbalizations, sudden limb movements, or other parasomnias (undesirable phenomena that occur mainly or only during sleep). The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-electroencephalogram (EEG) monitoring.The diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is established in individuals with the above clinical features and/or a disease-causing mutation in CHRNA4, CHRNB2, or CHRNA2.Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8-11 Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Steinlein et al 1997, Oldani et al 1998, Provini et al 1999, Picard et al 2000]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes.Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. Interictal sleep EEG may show infrequent epileptiform discharges. Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial nocturnal frontal lobe epilepsy [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000]. The term ADNFLE should only be applied if the family history is positive for other affected individuals and/or if a disease-causing mutation has been identified in either CHRNA4, CHRNB2, or CHRNA2. Molecular Genetic TestingGenes. The genes in which mutations are known to cause ADNFLE [Steinlein et al 1997, Hirose et al 1999, Saenz et al 1999, Gambardella et al 2000, Phillips et al 2000, Steinlein et al 2000, Diàz-Otero et al 2001, Phillips et al 2001, Cho et al 2003, Rozycka et al 2003, Aridon et al 2006]: CHRNA4, encoding the α4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR); associated with type 1 ADNFLECHRNB2, encoding the β2 subunit of the nAChR; associated with type 3 ADNFLECHRNA2, encoding α2 subunit of the (nAChR; associated with type 4 ADNFLECRH, encoding corticotropin-releasing hormoneEvidence for locus heterogeneity. Families with the ADNFLE phenotype and without mutations in CHRNA4, CHRNB2, or CHRNA2 have been described, demonstrating genetic heterogeneity [De Marco et al 2007]. A potential ADNFLE locus has been mapped in one family to chromosome 15q24, which is close to the sites of the gene cluster encoding the α3, α5, and β4 subunits of the nicotinic acetylcholine receptors (nAChR) (genes: CHRNA3, CHRNA5, and CHRNB4). In other families, linkage to CHRNA4, CHRNB2, CHRNA2, CRH, or the 15q24 locus has not been established, suggesting the existence of additional genes associated with ADNFLE [Phillips et al 1998, Tenchini et al 1999, Cho et al 2003]. Absence of linkage to nine other neuronal nicotinic acetylcholine receptor subunit genes expressed in brain was demonstrated in four unrelated Italian families [Bonati et al 2002]. Clinical testing Sequence analysis of CHRNA4, CHRNB2, and CHRNA2 identifies mutations in only approximately 20% of individuals with a positive family history of ADNFLE [Ottman et al 2010] and fewer than 5% of individuals who have no other family members with nocturnal frontal lobe epilepsy. Slightly fewer mutations are reported in CHRNB2 compared to CHRNA4. Mutations in CHRNA2 are rare.Table 1. Summary of Molecular Genetic Testing Used in Autosomal Dominant Nocturnal Frontal Lobe EpilepsyView in own windowADNFLE TypeGene SymbolProportion of ADNFLE Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityPositive Family HistoryNegative Family History1CHRNA410%-20%RareSequence of select exonsSequence variants ¹ in exon 5ClinicalSequence analysisSequence variants ^{1Deletion / duplication analysis 2Exonic or whole-gene deletion; none reported3CHRNB2Fewer than in CHRNA4Rare 3Sequence of select exons Sequence variants 1 in exon 5ClinicalSequence analysis Sequence variants 1Deletion / duplication analysis 2Exonic or whole-gene deletion; none reported4CHRNA2Rare 40%Sequence analysisSequence variants 1ClinicalNACRHUnknown 50%Sequence analysisSequence variants 1Research only1. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.3. Reported in one individual [Liu et al 2011] 4. Reported in one family [Aridon et al 2006]5. Reported in three families [Combi et al 2005] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband detection of a mutation in CHRNA4, CHRNB2, or CHRNA2 is required. Mutations reported to date in CHRNA4 or CHRNB2 are in exon 5 and reported mutations in CHRNA2 are in exon 6. Thus, sequence analysis of these three exons is recommended as a first step. There is not sufficient clinical information to determine which gene should be tested first. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in CHRNA4, CHRNB2, and CHRNA2.}

Natural HistoryAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Within a family, the manifestations of the disorder may vary considerably [Hayman et al 1997]; individuals with subtle manifestations may not present for medical attention. Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE. A high incidence of true parasomnias (undesirable phenomena that occur mainly or only during sleep) has been reported in relatives of those with ADNFLE [Provini et al 1999].Seizures may occur in any stage of sleep [Oldani et al 1996, Steinlein et al 1997, Provini et al 1999], although typically in clusters in non-REM sleep, most commonly in stage two sleep [Oldani et al 1998, Provini et al 1999]. The affected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event. A minority of individuals experience daytime seizures, typically during a period of poor seizure control. The seizures are often stereotyped and brief (5 seconds to 5 minutes) [Oldani et al 1996, Thomas et al 1998, Nakken et al 1999, Provini et al 1999, Ito et al 2000, Picard et al 2000]. They vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements. Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. A sense of difficulty breathing and hyperventilation may occur, as well as vocalization, clonic features, urinary incontinence, and secondary generalization. Some individuals experience an aura, which may be nonspecific or may consist of fear, a shiver, vertigo, or a feeling of falling or being pushed. The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration [Oldani et al 1998, Provini et al 1999] are “paroxysmal arousals,” “paroxysmal dystonia,” and “episodic wandering.” ADNFLE is lifelong but not progressive. Onset ranges from infancy to adulthood. About 80% of affected individuals develop ADNFLE in the first two decades of life [Oldani et al 1998, Picard et al 2000]; mean age of onset is ten years. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time; for example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood. Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010]. Picard et al [2009] found below-normal general intellect in 45% of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE with nicotinic receptor mutations. It is suggested that certain nAChR mutations could be associated with an increased risk for such symptoms [Steinlein et al 2012].

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been consistently identified. Steinlein et al [2012] suggested that certain nAchR mutations may be associated with an increased risk for cognitive dysfunction. Marked intrafamilial variation in severity is seen, the reasons for which are unknown.

Differential DiagnosisThe differential diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADFLNE) includes conditions of varied etiology.Normal sleep is characterized by periodic arousals, and occasionally other sleep-related movements or phenomena such as nightmares [Phillips et al 1998]. Other parasomnias (disorders in which undesirable physical and mental phenomena occur mainly or exclusively during sleep [American Academy of Sleep Medicine 2001]) to be considered include: Pavor nocturnus (night terrors), a common childhood syndrome, is characterized by attacks of extreme fear and distress that occur one or two hours after the child falls asleep. The child is unaware during the attack, which lasts five to ten minutes, and is amnesic for the event the following day [Schenck & Mahowald 2000]. Benign somnambulism (sleep walking) is not accompanied by abnormal motor behavior or dystonia and is usually a self-limiting disorder of childhood. Somnambulism is often familial. Hysteria is often considered because the individual retains awareness during the attacks, which can be bizarre. Clues to the organic nature of attacks are the occurrence during sleep and the stereotyped semiology (sequence of observed events during the attack). Familial paroxysmal kinesigenic dyskinesia (familial PKD) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism, are sometimes preceded by an aura, and do not involve loss of consciousness. Attacks can be as frequent as 100 per day to as few as one per month. Duration of attacks is typically a few seconds to five minutes, but can be several hours. Familial PKD has been associated with infantile, but not adult-onset, seizures. Age of onset is typically in childhood and adolescence, but ranges from four months to 57 years. Familial PKD is predominantly seen in males. Mutations in PRRT2 have been reported as causative of a subset of cases of familial PKD. The other gene(s) associated with PKD have not been identified. Inheritance is autosomal dominant. Familial paroxysmal nonkinesigenic dyskinesia (familial PNKD) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, coffee or tea, excitement, stress fatigue, or chocolate. Attacks involve dystonic posturing with choreic and ballistic movements, are sometimes accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Age of onset is typically in childhood or early teens, but can be as late as age 50 years. MR1, the gene encoding myofibrillogenesis regulator 1, is the only gene known to be associated with familial PNKD. Inheritance is autosomal dominant. Familial partial epilepsy with variable foci (FPEVF) is a hereditary partial epilepsy syndrome in which some family members may have frontal lobe epilepsy with a nocturnal pattern [Phillips et al 1998, Steinlein 1999]. FPEVF is distinguished by other family members having partial epilepsy emanating from other cortical regions. Periodic limb movement disorder (nocturnal myoclonus) affects the flexor muscles of the lower limbs and is characterized by segmental motor activity in muscles that recurs every 20-30 seconds. Brief stationary movements may be followed by myoclonic or repetitive clonic jerks that coincide with the periodic K-complexes of light sleep. Restless legs syndrome is often accompanied by segmental motor activity and may be a spinal cord-mediated disorder. REM sleep disorders may include prominent motor and verbal manifestations that are often of unknown cause or secondary to other neurologic disorders. REM sleep disorders typically occur in men ages 55-60 years. Polysomnography is a useful diagnostic tool.Respiratory disorders such as asthma may be considered because of difficulty breathing. Obstructive sleep apnea may be considered in individuals complaining of daytime sleepiness who are not aware of their nocturnal attacks. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE):In addition to the evaluation for epilepsy, cognitive and behavioral assessment may help determine the extent of disease. Medical genetics consultation is appropriate.Treatment of ManifestationsCarbamazepine is the antiepileptic drug (AED) of choice for ADNFLE, although no controlled trials have been conducted. In about 70% of individuals with ADFLNE, carbamazepine is associated with remission of seizures, often with relatively low doses. However, individuals with ADNFLE associated with the CHRNA4 mutation p.Ser284Leu respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004].Resistance to AEDs occurs in about 30% of affected individuals. Intrafamilial variation in pharmaco-responsiveness occurs; therefore, all appropriate AEDs should be tried. Vagal nerve stimulation may be considered for individuals with resistance to AEDs [Carreño et al 2010].SurveillanceAnnual or biannual evaluation of EEGs to monitor disease progression is appropriate. Evaluation of Relatives at RiskA medical history to seek evidence of affected status should be elicited from relatives at risk so that treatment can be initiated if appropriate.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nocturnal Frontal Lobe Epilepsy, Autosomal Dominant: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCHRNA420q13​.33Neuronal acetylcholine receptor subunit alpha-4CHRNA4 homepage - Mendelian genesCHRNA4CHRNB21q21​.3Neuronal acetylcholine receptor subunit beta-2CHRNB2 homepage - Mendelian genesCHRNB2CHRNA28p21​.2Neuronal acetylcholine receptor subunit alpha-2CHRNA2 homepage - Mendelian genesCHRNA2CRH8q13​.1CorticoliberinCRH homepage - Mendelian genesCRHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nocturnal Frontal Lobe Epilepsy, Autosomal Dominant (View All in OMIM) View in own window 118502CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 2; CHRNA2 118504CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4 118507CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 2; CHRNB2 122560CORTICOTROPIN-RELEASING HORMONE; CRH 600513EPILEPSY, NOCTURNAL FRONTAL LOBE, 1; ENFL1 603204EPILEPSY, NOCTURNAL FRONTAL LOBE, 2; ENFL2 605375EPILEPSY, NOCTURNAL FRONTAL LOBE, 3; ENFL3 610353EPILEPSY, NOCTURNAL FRONTAL LOBE, 4; ENFL4Molecular Genetic PathogenesisThe neuronal nicotinic acetylcholine receptor is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by CHRNA4 and CHRNB2, respectively. The most common configuration is (α4)₂(β2)₃ subunits; that is, two α4 and three β2 subunits. The receptor is widely distributed in the brain, including the frontal lobes. It is thought that the receptor is a presynaptic modulator of other neurotransmitter systems, including gamma-amino butyric acid (GABA), glutamate, and dopamine, and therefore may have variable effects on excitatory and inhibitory pathways [Kuryatov et al 1997, Bertrand 1999, Buisson et al 1999, Picard et al 1999]. The second transmembrane domain of the receptor forms the ion channel pore and is the site of most of the mutations implicated in ADNFLE. Mutations in CHRNA4 and CHRNB2 associated with ADNFLE occur in highly conserved amino acids and alter the function of the resulting receptors. Functional studies of different mutations provide conflicting results although an increase in acetylcholine (Ach) sensitivity in vitro is typical for known ADNFLE-associated mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001, di Corcia et al 2005]; thus, the mechanism whereby the mutations cause ADNFLE is poorly understood. The corticotropin-releasing hormone is widely distributed throughout the central nervous system. CRH acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviors including sleep and arousal. Two new nucleotide variations in the promotor region were reported [Combi et al 2005, Shimmin et al 2007].CHRNA4 Normal allelic variants. CHRNA4 has six exons distributed over approximately 17 kb of genomic DNA [Steinlein et al 1996]. The main part of the coding region is distributed in exon 5 [Steinlein et al 1996]. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997]. Pathologic allelic variants. See Table 2. In a sporadic NFLE case, Chen et al [2009] identified a novel mutation in CHRNA4 that causes an α4-Arg336His amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. Certain mutations have been observed in many different countries; these mutations occurred independently [Steinlein et al 2000, Hwang et al 2011].Table 2. Selected CHRNA4 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.839C>Tp.Ser280Phe ^{1NM_000744​.5
NP_000735​.1c.851C>Tp.Ser284Leu 2c.878C>Tp.Thr293Ile 3c.870_872dupGCTp.Leu291dup 4c.1007G>Ap.Arg336His 5See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Four families [Saenz et al 1999, Steinlein et al 2000, McLellan et al 2003]2. Hirose et al [1999], Rozycka et al [2003]3. Leniger et al [2003]4. Steinlein et al [1997]5. Chen et al [2009]For more information, see Table A.Normal gene product. Each nicotinic acetylcholine receptor subunit has a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region [Elliott et al 1996]. The α subunits are characterized by the presence of a pair of cysteine residues (Cys161 and Cys175, NP_000735.1) that are presumed to function as part of the ACh binding site when the α4 subunits are complexed as a heterologous pentamer with the β subunits [Figl et al 1998]. Abnormal gene product. Functional studies of different mutations provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-causing mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001]; hence gain of function of nAChR may be a contributing mechanism of developing ADNFLE. Studies on mutated nAchR demonstrated an increased sensitivity to carbamazepine [Picard et al 1999].CHRNB2 Normal allelic variants. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997]. Pathologic allelic variants. Various mutations resulting in changes in the highly conserved region of the conducting pore or transmembrane domain are described. A novel mutation in CHRNB2, p.Val337Gly, located between transmembrane domains M3 and M4, was identified in a sporadic NFLE case [Liu et al 2011]. See Table 3.Table 3. Selected CHRNB2 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.859G>Cp.Val287Leu 1NM_000748​.2
NP_000739​.1c.859G>Tp.Val287Leu 2c.859G>Ap.Val287Met 3c.901C>Gp.Leu301Val 4c.923T>Cp.Val308Ala 4c.936C>Gp.Ile312Met 5c.1010T>Gp.Val337Gly 6See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. De Fusco et al [2000]2. Kurahashi et al [unpublished observation]3. Diàz-Otero et al [2001], Phillips et al [2001]4. Hoda et al [2008]5. Bertrand et al [2005]6. Liu et al [2011]For more information, see Table A.Normal gene product. CHRNB2 encodes the β2 subunit of nAChR. The β2 subunit is composed of 503 amino acids. CHRNB2 is similar to CHRNA4, but the β subunits encoded by the genes are defined by the lack of paired cysteine residues [Elliott et al 1996]. Abnormal gene product. Functional studies of different mutations provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-associated mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001]; hence, gain of function of nAChR may be a contributing mechanism of developing ADNFLE.CHRNA2Normal allelic variants. CHRNA2 has seven exons distributed over approximately 19 kb of genomic DNA. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997]. Pathologic allelic variants. One mutation resulting in changes in the highly conserved region of the first transmembrane domain is described [Aridon et al 2006]. See Table 4.Table 4. Selected CHRNA2 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences c.836T>Ap.Ile279Asn 1NM_000742​.3
NP_000733​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Aridon et al [2006]Normal gene product. CHRNA2 encodes the α2 subunit of nAChR. The α2 subunit is composed of 529 amino acids. CHRNA2 is similar to CHRNA4.Abnormal gene product. The CHRNA2 mutation increases the receptor sensitivity to acetylcholine, and gain of function of nAChR may be a contributing mechanism of developing ADNFLE [Aridon et al 2006, Hoda et al 2009]. Carbamazepine and oxcarbazepine produce a non-competitive channel inhibition in heteromeric neuronal nicotinic receptors including mutated α2 subunits as well as wild α2 subunits, but the different heteromeric nicotinic receptors exhibit distinct pharmacologic properties [Di Resta et al 2010]. CRHNormal allelic variants. Normal allelic variants of CRH have been described [Shimmin et al 2007].Pathologic allelic variants. Two variants in the promotor region were reported [Combi et al 2005]. See Table 5.Table 5. Selected CRH Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences c.-1166G>C
g.67,090,878NoneNM_000756​.1
NC_000008​.10c.-1470C>A
g.67,091,183NoneSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. CRH is composed of 196 amino acids.Abnormal gene product. In vitro assays demonstrated that these variants result in altered levels of gene expression. The luciferase assay showed stronger promotor activity for the g.-1470C>A variation, whereas reduction of the promotor activity was detected for the g.-1166G>C mutation [Combi et al 2005].}