OCULODIGITOESOPHAGODUODENAL SYNDROME
MICROCEPHALY-OCULO-DIGITO-ESOPHAGEAL-DUODENAL SYNDROME
MMT SYNDROME
FEINGOLD SYNDROME
ODED SYNDROME
MICROCEPHALY AND DIGITAL ABNORMALITIES WITH NORMAL INTELLIGENCE
FGLDS1
MICROCEPHALY, MENTAL RETARDATION, AND TRACHEOESOPHAGEAL FISTULA SYNDROME
DIGITAL ANOMALIES WITH SHORT PALPEBRAL FISSURES AND ATRESIA OF ESOPHAGUS OR DUODENUM
ODED
MODED
Feingold syndrome is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly ... Feingold syndrome is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients (summary by Teszas et al., 2006). - Genetic Heterogeneity of Feingold Syndrome Feingold syndrome-2 (FGLDS2; 614326) is caused by hemizygous deletion of the MIR17HG gene (609415) on chromosome 13q31.3.
Feingold (1975) reported a father, son, and grandmother with microcephaly, hand abnormalities, tracheoesophageal fistula, duodenal atresia, and normal intelligence. Feingold (1978) reported a mother and daughter with similar findings except for the absence of tracheoesophageal fistula and duodenal ... Feingold (1975) reported a father, son, and grandmother with microcephaly, hand abnormalities, tracheoesophageal fistula, duodenal atresia, and normal intelligence. Feingold (1978) reported a mother and daughter with similar findings except for the absence of tracheoesophageal fistula and duodenal atresia. Konig et al. (1990) described an affected mother and son with what they designated microcephaly, mesobrachyphalangy, and tracheoesophageal fistula (MMT) syndrome. Brunner and Winter (1991) reported 2 families with an autosomal dominant syndrome of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and esophageal/duodenal atresia. The hand anomalies included flexion deformity of the middle finger and clinodactyly of the second and fifth fingers. Foot anomalies included bilateral syndactyly of toes 2-3 and 4-5. In the first family, the mother and 2 sons were affected, and 8 other family members had the same abnormalities of the hands and feet; 3 of them had had operations in the neonatal period for esophageal or duodenal atresia or both. There were no instances of male-to-male transmission. In the second family, a mother and son and daughter were affected. There was no consanguinity in either family. The phenotype of the syndrome was similar to that observed with 13q22-qter deletion, but chromosome analysis detected no structural abnormality in these familial cases. Feingold et al. (1997) reported on 6 'new' families (12 patients) with this syndrome, updated the findings of the original families, and more clearly defined the syndrome. The most common findings were hand abnormalities, microcephaly, short and/or narrow palpebral fissures, broad nasal bridge, anteverted nostrils, ear abnormalities, and micrognathia. The features showed a significant amount of intrafamilial variability, especially as it related to the gastrointestinal findings. Although the first patients reported, who were very young, exhibited no developmental delay, they subsequently developed learning problems, and 87% of the 12 patients had mental retardation or learning difficulties. Typical hand findings, short second and fifth fingers, and clinodactyly and hypoplasia of the middle phalanx were pictured. Autosomal dominant inheritance was supported by the finding of male-to-male transmission in the family reported by Feingold (1975); in 8 of the 11 reported families, there was transmission through at least 2 generations. Innis et al. (1997) reported what appeared to be the same condition in a family with 6 and probably 8 affected members in 3 generations, including instances of male-to-male transmission. They referred to the condition as autosomal dominant microcephaly with normal intelligence, short palpebral fissures, and digital anomalies. Affected individuals consistently had microcephaly (OFC less than third centile) and short palpebral fissures; however, there was considerable variability and individual asymmetry in the defects of the limbs. Major limb anomalies were hypoplasia, slender thumbs with limited flexion at the distal interphalangeal joints of thumbs and some fingers, thin proximal first metacarpals, and short middle phalanges of the index and fifth fingers. None of the affected persons had polyhydramnios or duodenal atresia, but 1 individual had a history of tracheoesophageal fistula. Taken together with previous reports, the risk for tracheoesophageal fistula and/or duodenal atresia in this disorder was 8 in 29, or approximately 28%. Frydman et al. (1997) described 4 families with what they considered to be the same disorder, which they called microcephaly-oculo-digito-esophageal-duodenal syndrome, or MODED. The phenotype is inherited as an autosomal dominant and includes microcephaly, type A brachydactyly, variable learning disabilities, short stature, duodenal atresia, patent ductus arteriosus (see 607411), hallux valgus, and a variety of digital anomalies. The authors reviewed previous reports, including their own observations. Penetrance of digital anomalies was almost complete. Microcephaly was present in 78% of known cases. Esophageal and duodenal atresias were found in 25% of known cases, but correction for ascertainment bias gave an estimate of 16.6%. Learning disabilities were seen in 31% of patients. Courtens et al. (1997) reported a seventh family with Feingold syndrome. The propositus was a male infant with esophageal and duodenal atresia, brachymesophalangy of the fifth fingers, bilateral syndactyly of toes 4-5 (and 2-3), relative microcephaly, and facial anomalies. His mother also had microcephaly, similar facial appearance, short fifth fingers with single flexion crease, syndactyly of toes 4-5, and learning disabilities. A sister and brother of the mother and her mother had the same phenotype. A review of the 7 families with Feingold syndrome demonstrated that intestinal (esophageal/duodenal) atresia/obstruction occurs in approximately one-third of patients with Feingold syndrome. Kawame et al. (1997) described 4 patients (2 boys and their mother and an unrelated girl) with microcephaly, normal intelligence, and digital abnormalities. The hand abnormalities were characterized by brachydactyly with radial clinodactyly of the fourth and fifth fingers, ulnar clinodactyly of the second fingers, and an increased space between the second and third fingers associated with an abnormal palmar crease that extended to the ulnar border. The foot abnormalities included short toes with syndactyly of the fourth and fifth toes. The mother had normal intelligence, and her sons and the unrelated girl had normal development. Kawame et al. (1997) noted similar findings in the patients reported by Feingold (1975) and Feingold et al. (1997), but suggested that the lack of gastrointestinal anomalies indicated that their 4 patients may have had a different autosomal dominant disorder. Buttiker et al. (2000) described a father and daughter with characteristic features of Feingold syndrome including microcephaly, short palpebral fissures, brachydactyly with clinodactyly of fifth fingers, and bilateral syndactyly of second to third and fourth to fifth toes. The infant presented with long-gap esophageal atresia without fistula. Her father, who had short stature and learning disabilities, had congenital imperforate anus with a rectovesical fistula. The authors thought that this was first report of distal intestinal atresia in Feingold syndrome. Shetty et al. (2000) described a 12-year-old girl with features of both the syndrome of microcephaly, mesobrachyphalangia, and tracheoesophageal fistula and Rett syndrome (312750). They suggested that this combination may constitute a new contiguous gene syndrome. However, the mapping of Rett syndrome to the X chromosome and the identification of the specific gene defect makes it unlikely that this was conventional Rett syndrome occurring as a contiguous gene syndrome with MMT syndrome, which maps to chromosome 2. Piersall et al. (2000) reported an additional family, a father and 2 sibs, with ODED syndrome, which associates microcephaly, abnormalities of the hands and feet, shortened palpebral fissures, tracheoesophageal fistula, and duodenal atresia. Vertebral anomalies were noted in this family. The sacral spine demonstrated a sagittal cleft at the body of S4 and absence of S5. His father had blocked vertebra of C5, 6, and 7 and neural arch fusion on the left of the 6th and 7th vertebrae. Shaw-Smith et al. (2005) and Shaw-Smith (2006) described a boy and his father with Feingold syndrome. They pictured short palpebral fissures and periorbital fullness, mild bilateral fifth finger clinodactyly, and in the father, bilateral clinodactyly of second and fifth fingers with brachymesophalangy of the second fingers. Shaw-Smith et al. (2005) observed short stature in the father and son and noted that of 18 cases of Feingold syndrome in the literature for which height was recorded, 4 had height at or below the 3rd centile, and 9 had height at or below the 10th centile; the authors suggested that short stature is likely to be a phenotypic feature of the syndrome. Teszas et al. (2006) reported a 4-year-old boy with classic features of Feingold syndrome associated with a pathogenic mutation in the MYCN gene (164840.0004). The patient's mother and grandmother both carried the mutation and had microcephaly, fifth finger clinodactyly, partial syndactyly of the toes, and normal intelligence, consistent with microcephaly and digital abnormalities with normal intelligence syndrome as defined by Kawame et al. (1997). The mother also had chronic nephritis, renal insufficiency, and hypertension. Teszas et al. (2006) suggested that microcephaly and digital abnormalities with normal intelligence represents a milder form of Feingold syndrome. Blaumeiser et al. (2008) reported monozygotic female twins with Feingold syndrome associated with a mutation in the MYCN gene (164840.0006). Both had the classic finger and toe malformations, hypertelorism, epicanthal folds, and developmental delay with occasional aggressive behavior. One sib had sensorineural deafness, and the other had duodenal atresia. Family history and genetic analysis showed that the mother and maternal grandfather also carried the mutation, but had only finger and toe anomalies. A maternal uncle of the twins also carried the mutation and had mental impairment, finger and toe anomalies, and structural renal problems. Blaumeiser et al. (2008) noted the wide phenotypic variability in this family. Kocak et al. (2009) reported a Turkish boy with Feingold syndrome confirmed by genetic analysis. He had microcephaly, frontal balding, upslanting and short palpebral fissures, choanal atresia, micrognathia, and large ears. He had bilateral hypoplastic middle phalanges of the second and fifth fingers, syndactyly of the second and third toes, and overriding of the fourth and fifth toes. He presented at age 3.5 months with seizures and vomiting. Family history revealed an older sib with esophageal atresia who died, as well as 3 other miscarriages. The father, who also carried the mutation, had a small head and severe digital anomalies, with brachydactyly, brachymesophalangy of all fingers, and partial skin syndactyly of the second and third toes.
In a previously unreported family with Feingold syndrome, van Bokhoven et al. (2005) found that affected members carried a microdeletion, which spanned a maximum interval of 1.2 Mb and encompassed the MYCN gene but no other known or ... In a previously unreported family with Feingold syndrome, van Bokhoven et al. (2005) found that affected members carried a microdeletion, which spanned a maximum interval of 1.2 Mb and encompassed the MYCN gene but no other known or predicted gene, making it an excellent candidate for Feingold syndrome. The MYCN gene had been shown to be activated by Sonic hedgehog (Shh; 600725) signaling and several lines of evidence suggest that the Shh pathway is disrupted in TEF/EA (Litingtung et al., 1998; Kenney et al., 2003; Oliver et al., 2003). In a cohort of 23 unrelated families with Feingold syndrome, van Bokhoven et al. (2005) sequenced the MYCN gene and identified 12 different heterozygous mutations in 15 families, including 3 different missense mutations at 2 adjacent arginine residues (164840.0001-164840.0003). Marcelis et al. (2008) analyzed the MYCN gene in 93 patients from 50 families with a strong clinical suspicion of Feingold syndrome and identified 16 heterozygous mutations in 17 families with a total of 26 patients, including mutations in exon 2, which had not previously been reported (see, e.g., 164840.0007). The authors reviewed the clinical features of the 77 mutation-positive patients reported to date and compared them with the largest previous overview (Celli et al., 2003), and found that digital anomalies involving brachymesophalangy and toe syndactyly were the most consistent features, present in 100% and 97% of patients, respectively, whereas small head circumference was present in 89% of cases. Gastrointestinal atresia was the most important major congenital anomaly (55%), but renal and cardiac anomalies were also frequent (18% and 15%, respectively). Marcelis et al. (2008) suggested that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.
The clinical features of Feingold syndrome 1 (FS1) have been reviewed by Marcelis et al [2008]. Major features:...
DiagnosisClinical Diagnosis The clinical features of Feingold syndrome 1 (FS1) have been reviewed by Marcelis et al [2008]. Major features:Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly) Microcephaly (occipito-frontal circumference <10th centile) Short palpebral fissures Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI).A diagnosis of FS1 can be made when a MYCN mutation or deletion is identified. In the absence of a MYCN abnormality a clinical diagnosis of FS1 should still be considered in the presence of typical digital anomalies with microcephaly or gastrointestinal atresia or typical facial features. Molecular Genetic Testing Gene. MYCN is the only gene in which mutations are known to cause Feingold syndrome 1 [van Bokhoven et al 2005] Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Feingold Syndrome 1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMYCN 2Sequence analysisSequence variants 365% 4ClinicalDeletion/duplication testing 5Exonic and partial-gene deletions10% 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Typical digital anomalies were absent in individuals with FS1 in whom no MYCN mutation was identified [Marcelis et al 2008], whereas these typical digital anomalies are present in more than 95% of individuals with FS1 who have MYCN mutations. 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Sequence analysis of all three exons of MYCN detected mutations in 65% of individuals/families with a clinical suspicion of Feingold syndrome 1 [Marcelis et al 2008].5. 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.6. Deletion/duplication testing detects mutations in 10% of individuals/families with Feingold syndrome 1 [Marcelis et al 2008]. 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 Strategy Confirming/establishing the diagnosis in a probandWhen a diagnosis of FS1 is suspected, molecular testing can begin with sequence analysis of MYCN. If no sequence variant is identified, additional deletion/duplication analysis can be performed.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with (germline) mutations in MYCN.Note: Somatic amplification of human N-Myc, now formally denoted as MYCN, is associated with poor prognosis in neuroblastoma and can be found in approximately 25% of all cases [Lu et al 2003].
Feingold syndrome 1 (FS1) as described by Feingold [1975] and Brunner & Winter [1991] is characterized by digital anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias, and learning disability. The features are summarized in Table 2. ...
Natural History Feingold syndrome 1 (FS1) as described by Feingold [1975] and Brunner & Winter [1991] is characterized by digital anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias, and learning disability. The features are summarized in Table 2. Table 2. Features in Feingold Syndrome 1View in own windowFeingold Syndrome 1 Feature% of Persons with FeatureDigital anomalies Brachymesophalangy100% Toe syndactyly97% Thumb hypoplasia17%Microcephaly89%Facial dysmorphism Short palpebral fissures73% Micrognathia32%Atresia Gastrointestinal55% Esophageal32% Duodenal31% Jejunal3% Anal2% Multiple12%Mild learning deficit51%Other Stature <10th centile60% Renal abnormalities18% Cardiac abnormalities15% PDA12% Other10% Hearing loss10%Marcelis et al [2008]The most consistent findings are digital anomalies. Brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) has been present in 100% of individuals reported to have a MYCN mutation. Toe syndactyly (2-3 and/or 4-5) has been reported in 97%. Thumb hypoplasia is also common. See Figures 1, 2, and 3.FigureFigure 1. Typical brachymesophalangy in an adult with FS1 FigureFigure 2. X-ray showing typical brachymesophalangy (digits 2 and 5) and thumb hypoplasia FigureFigure 3. Typical syndactyly of 2nd and 3rd or 4th and 5th toe Gastrointestinal atresia (esophageal and/or duodenal) is a cause of major medical concern in FS1 and requires immediate surgical intervention (see Management). Cardiovascular and renal malformations are seldom severe in FS1.Mild learning deficit is frequent in FS1. Clear intellectual disability is rare but intelligence is below average when compared to the general population and healthy, unaffected family members. Some reports show that growth is impaired in FS1 [Shaw-Smith et al 2005]. Obvious short stature (height <3rd centile) is uncommon but average is decreased compared to the general population.Associated features that occur in fewer than 50% of affected individuals include renal and cardiac abnormalities and hearing loss.
No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift mutations....
Genotype-Phenotype Correlations No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift mutations.
Differential DiagnosisTable 3. Feingold Syndrome 1: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM NumberFeingold syndrome 1164280 MYCN, NMYC, ODED, MODED 164840 Feingold syndrome 2 614326 MIR17HG, MIRH1, MIHG1, MIRHG1, C13orf25, FGLDS2 609415 Data from Online Mendelian Inheritance in ManFeingold syndrome 2 is caused by hemizygous deletions of chromosome 13q31.3 including MIR17HG [De Pontual et al 2011]. Individuals with this deletion share many features with Feingold syndrome 1 (FS1), including microcephaly, mild growth retardation and the skeletal findings of Feingold syndrome, brachymesophalangy, toe syndactyly and thumb hypoplasia. Important differences are the lack of gastrointestinal abnormalities and short palpebral fissures in Feingold syndrome 2 in the limited number of individuals described at present [De Pontual et al 2011]. See Esophageal Atresia/Tracheoesophageal Fistula Overview.VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal and limb abnormalities) shows considerable overlap with FS1, but the two should be distinguishable by the presence of microcephaly, brachymesophalangy, and toe syndactyly in FS1. Esophageal atresia, heart defects, and renal abnormalities can be seen in CHARGE syndrome. Thumb hypoplasia and other congenital anomalies are seen in Fanconi anemia. Brachymesophalangy in FS1 is very similar to brachydactyly type A4. Although no mutations in MYCN have been identified in brachydactyly type A4, molecular genetic testing of MYCN could be considered in families with brachydactyly type A4.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).
To establish the extent of disease in an individual diagnosed with Feingold syndrome 1 (FS1), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Feingold syndrome 1 (FS1), the following evaluations are recommended:Cardiac investigation (echocardiogram)Renal ultrasound to evaluate for structural abnormalities Audiometry for the possibility of hearing lossNeuropsychological evaluation if there are concerns about psychomotor development Analysis of the family pedigree for other possible affected individualsMedical genetics consultationTreatment of ManifestationsAppropriate treatment includes the following:Surgical treatment of gastrointestinal atresia when present Follow up and treatment of possible cardiac and renal anomaliesTreatment for significant hearing lossDevelopmental or educational intervention for children with learning difficultiesPrevention of Secondary ComplicationsProphylactic antibiotics may be needed when cardiac or renal anomalies are present.SurveillanceRoutine follow up for any of the above-listed medical issues by the appropriate specialist is warranted.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Because of the risk for major congenital abnormalities of the gastrointestinal tract, heart, and kidney, high-resolution ultrasound investigations (including fetal echocardiogram) are advised in any pregnancy in which one of the parents is known to be affected. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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. Feingold Syndrome 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMYCN2p24.3N-myc proto-oncogene proteinCatalogue of Somatic Mutations in Cancer (COSMIC)MYCNData 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 Feingold Syndrome 1 (View All in OMIM) View in own window 164280FEINGOLD SYNDROME 1; FGLDS1 164840V-MYC AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED; MYCNNormal allelic variants. See Table 4. Human MYCN consists of three exons. Although exon 1 does contain a potential translation start codon, initiation of MYCN protein synthesis commences at the first ATG codon in exon 2 because of an internal ribosome entry site in the 5’-untranslated region [Jopling & Willis 2001]. An alternative transcript consisting of exons 1 and 3 only has been described. This transcript encodes a truncated MYCN isoform, denoted MYCN, which is initiated by using the potential start codon in exon 1 [van Bokhoven et al 2005]. A variant in exon 1 (p.Gln22*), which affects only the MYCN isoform, was described in an affected individual but did not segregate with the disease in the family [Marcelis et al 2008]. Therefore, the p.Gln22* change of the MYCN isoform is considered to be a normal allelic variant. These data suggest that the MYCN isoform contributes little or nothing to the pathogenesis of Feingold syndrome 1 (FS1). Somatic amplification of human N-Myc, now formally denoted as MYCN, is associated with poor prognosis in neuroblastoma and can be found in approximately 25% of neuroblastoma cases [Lu et al 2003]. Pathologic allelic variants. See Table 4. All mutations currently identified are present in either exon 2 or 3 of MYCN. No pathogenic mutations in exon 1 have been described.Table 4. Selected MYCN Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference SequencesNormalc.64C>Tp.Gln22*NM_005378.4 NP_005369.2 Pathologicc.217G>Tp.Glu73*See 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. The Myc family of proteins is well known for its role in oncogenic processes. Members of this family include c-Myc, N-Myc and L-Myc. N-myc was identified by homology with c-Myc in amplified sequences of neuroblastomas. The creation of knockout mice has revealed crucial roles for c-Myc and N-Myc in development as well. Mice deficient for either of these Myc genes die before embryonic day 11.5. Targeted inactivitation of murine N-myc has revealed a number of functions during development, including a role in branching morphogenesis in the lung, and roles in the development of the mesonephric tubules, the neuroepithelium, the sensory ganglia, the gut, the heart, and the limb [Charron et al 2002, Knoepfler et al 2002, Ota et al 2007]. Many of these structures are also affected in FS1. These phenotypic abnormalities are in line with the expression of the gene during development.Abnormal gene product. The occurrence of inactivating mutations of N-myc supports haploinsufficiency of N-myc proto-oncogene protein as a cause of FS1. All mutations affect the MYCN isoform of the gene.
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MYCN, which is initiated by using the potential start codon in exon 1 [van Bokhoven et al 2005]. A variant in exon 1 (p.Gln22*), which affects only the