DiagnosisClinical DiagnosisThe clinical diagnosis of Sotos syndrome can be made if an individual has a characteristic facial gestalt, a learning disability, and overgrowth [Rio et al 2003, Turkmen et al 2003, Cecconi et al 2005, Faravelli 2005, Tatton-Brown et al 2005b, Waggoner et al 2005]. Based on the analysis of more than 500 individuals with an NSD1 abnormality, these three cardinal features were shown to occur in at least 90% of affected individuals [Tatton-Brown et al 2005b]. Where an individual does not fulfill all three clinical criteria, the clinical suspicion of Sotos syndrome can be confirmed with genetic testing (see Molecular Genetic Testing). Characteristic facial appearance. The facial gestalt is the most specific diagnostic criterion for Sotos syndrome and also the feature most open to observer error and inexperience. The gestalt is most easily recognizable between ages one and six years. In older children and adults, the facial features, although still typical, can be more subtle [Allanson & Cole 1996, Tatton-Brown et al 2005b].
Typical facial features include malar flushing, sparse frontotemporal hair, high bossed forehead, downslanting palpebral fissures, a long narrow face, and prominent narrow jaw; the head is said to resemble an inverted pear. The facial shape is retained into adulthood, but with time the chin becomes squarer in shape and more prominent. Learning disability. Delay of early developmental milestones is very common and motor skills may appear particularly delayed because of the large size, hypotonia, and poor coordination. Language delay is also usually apparent [Ball et al 2005]. The great majority of affected individuals have some degree of intellectual impairment. However, the extent is highly variable, ranging from mild (in which children attend mainstream schools and are likely to be independent in adulthood) to severe (in which lifelong care and support are required) [Tatton-Brown et al 2005b]. Overgrowth. Approximately 90% of children have a height and/or head circumference two or more SD above the mean [Tatton-Brown et al 2005b]. Height may normalize in adulthood, but macrocephaly is usually present at all ages [Agwu et al 1999; Cole, personal communication]. TestingCytogenetic testing. Most affected individuals do not have a cytogenetic abnormality. Rarely, a cytogenetic abnormality such as a translocation involving 5q35 results in Sotos syndrome [Kurotaki et al 2002]. Molecular Genetic TestingGene. NSD1 is the only gene in which mutations are currently known to cause Sotos syndrome. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Sotos SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityJapaneseNon-JapaneseNSD1Sequence analysis / mutation scanning 2Sequence variants 3 ~12% 4 27%-93% 5ClinicalDeletion / duplication analysis 65q35 microdeletion encompassing NSD1 and NSD1 partial-gene deletions~50% 7, 8, 9~15% 8, 9FISH5q35 microdeletion encompassing NSD1 ~50% 4, 8, 10~10% 5, 8, 101. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Limited mutation screening has been undertaken in Japanese individuals [Kurotaki et al 2003, Miyake et al 2003, Tei et al 2006]. 5. The variability in detection rate reflects different eligibility criteria for screening [Douglas et al 2003, Rio et al 2003, Cecconi et al 2005, Faravelli 2005, Melchior et al 2005, Waggoner et al 2005, Saugier-Veber et al 2007]. An NSD1 detection rate of at least 90% was achieved when the clinical diagnosis of Sotos syndrome had been made by clinicians with expertise in the condition [Turkmen et al 2003, Tatton-Brown et al 2005b].6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.7. The contribution of partial-gene deletions to Sotos syndrome in Japanese individuals is currently unknown [Douglas et al 2005, Tatton-Brown et al 2005b].8. The microdeletions can be detected with equal sensitivity by FISH or other deletion/duplication analytic methods (e.g., multiplex ligation-dependent probe amplification [MLPA]) [Douglas et al 2003, Kurotaki et al 2003, Rio et al 2003, Turkmen et al 2003, Cecconi et al 2005, Tatton-Brown et al 2005a, Visser et al 2005, Waggoner et al 2005]. 9. Exonic/multiexonic deletions (i.e., deletion of one or more exons) are responsible for an estimated 5% of Sotos syndrome [Douglas et al 2005, Tatton-Brown et al 2005b]. Deletion/duplication analytic methods (see footnote 6) are required; typically, FISH cannot detect exonic/multiexonic gene deletions. Deletions encompassing exons 1 and 2 are most common, likely reflecting the high density of Alu repeats in the flanking sequences [Douglas et al 2005]. 10. Typically, FISH cannot detect exonic/multiexonic gene deletions.Interpretation of test results. All frameshift and nonsense mutations, splicing variants at consensus residues, partial-gene deletions, and microdeletions encompassing NSD1 are predicted to be pathogenic. Missense variants require more careful interpretation.De novo variants in a simplex case of Sotos syndrome are highly likely to be pathogenic. Pathogenic missense mutations typically occur at conserved, functionally relevant residues within protein domains [Tatton-Brown et al 2005b]. Missense variants outside conserved domains should be assumed to be normal variants in the absence of additional data in favor of pathogenicity (e.g., demonstration that the variant is de novo, results of a functional assay). 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 probandIf a diagnosis of Sotos syndrome is suspected, NSD1 molecular genetic testing should be considered to confirm the clinical diagnosis and to provide information about risk of recurrence. For individuals of non-Japanese ancestry, sequencing analysis is the first line of testing, followed by deletion/duplication or FISH analysis if the sequencing is does not identify a mutation. In individuals of Japanese ancestry, deletion/duplication or FISH analysis may be considered first.
Note: If a molecular diagnosis of Sotos syndrome has been made, x-rays for bone age and MRI scan of the brain are not required to confirm the diagnosis. If the clinical diagnosis of Sotos syndrome is uncertain or if molecular testing is negative, routine karyotype, array CGH, and molecular genetic testing for fragile X syndrome should be undertaken. (See Differential Diagnosis.)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) DisordersNSD1 abnormalities have high specificity and sensitivity for Sotos syndrome. Molecular genetic testing failed to identify mutations in NSD1 in more than 500 individuals with clinical diagnoses other than Sotos syndrome, including Marshall-Smith syndrome, autosomal dominant macrocephaly, nonspecific overgrowth, and individuals with macrocephaly in association with autism spectrum disorders [Turkmen et al 2003, Tatton-Brown et al 2005b, Waggoner et al 2005, Buxbaum et al 2007]. In rare cases, other clinical conditions that show overlap with Sotos syndrome and involve NSD1 mutations have been reported: A family with macrocephaly, tall stature, and normal intelligence [van Haelst et al 2005]An individual with Nevo syndrome [Kanemoto et al 2006] who has many clinical features consistent with Sotos syndrome. In addition, Nevo syndrome has been shown to be allelic to Ehlers-Danlos syndrome Type VIA. Both conditions are caused by biallelic mutations in PLOD1 [Giunta et al 2005].Two individuals with Beckwith-Wiedemann syndrome (BWS) [Baujat et al 2004] whose findings were not typical for BWS. Both showed considerable overlap with Sotos syndrome [Tatton-Brown & Rahman 2004].Six individuals with Weaver syndrome [Douglas et al 2003, Rio et al 2003]. Weaver and Sotos syndrome show greatest overlap in infancy, and in some of the individuals with Weaver syndrome and NSD1 mutations, the clinical phenotype evolved over time to be fairly classic of Sotos syndrome [Douglas et al 2003, Tatton-Brown et al 2005b]. Weaver syndrome has recently been shown to be caused by mutations in another histone methyl transferase gene, EZH2, providing further evidence that Weaver syndrome is a clinical entity distinct from Sotos syndrome [Tatton-Brown et al 2011, Gibson et al 2012].}

Natural HistoryBased on a review of 230 persons with NSD1 abnormalities, the clinical features of Sotos syndrome were classified as cardinal features (occurring in at least 90% of affected individuals), major features (occurring in 15%-89%), and associated features (occurring in ≥2% and <15% of persons) [Tatton-Brown et al 2005b]. It is very likely that additional associated features will be recognized as new cases are identified. It is also possible that some associated features (e.g., constipation) occur with greater frequency than appreciated now and thus could be reclassified as major features in the future.Cardinal Features (present in ≥90% of persons with Sotos syndrome)Characteristic facial appearance Learning disability OvergrowthMajor Features (present in 15%-89% of persons with Sotos syndrome)Behavioral problems Advanced bone age Cardiac anomalies Cranial MRI/CT abnormalities Joint hyperlaxity/pes planus Maternal preeclampsiaNeonatal complications Renal anomalies Scoliosis SeizuresCardinal Features Characteristic facial appearance. The facial gestalt of Sotos syndrome is evident at birth, but becomes most recognizable between ages one and six years. The head is dolichocephalic and the forehead broad and prominent. Often the hair in the frontotemporal region is sparse. The palpebral fissures are usually downslanting. Malar flushing may be present. At birth, the mandible appears small, but by childhood it is pointed, and in adulthood, often prominent and square [Allanson & Cole 1996, Tatton-Brown & Rahman 2004]. Learning disability. The majority of individuals with Sotos syndrome have some degree of intellectual impairment. The spectrum is broad and ranges from mild learning disability (affected individuals would be expected to live independently and have their own families) to severe learning disability (affected individuals would be unlikely to live independently as adults). It has been suggested that children with Sotos syndrome have difficulties with speech and language, particularly expressive language and articulation [Ball et al 2005]. The majority have mild-moderate learning disability; the level of intellectual impairment generally remains stable throughout life [Tatton-Brown et al 2005b; Authors, unpublished data].Growth. Sotos syndrome is associated with overgrowth of prenatal onset. Delivery is typically at term. The average birth length approximates to the 98th centile and the average birth head circumference is between the 91st and 98th centiles. Average birth weight is within the normal range (between the 50th and 91st centile). Before age ten years, affected children demonstrate rapid linear growth. They are often described as being considerably taller than their peers. Height and/or head circumference are generally 2 SD or more above the mean. However, growth is also influenced by parental heights and some individuals do not have growth parameters above the 98th centile [Cole & Hughes 1994, Tatton-Brown et al 2005b]. Data on final adult height are scarce; however, in both men and women, the range of final adult height is broad [Agwu et al 1999; Tatton-Brown & Rahman, unpublished data].The de Boer et al [2005] study of auxologic data supports that of Agwu et al [1999] and shows that individuals with NSD1 mutations have an increased arm span/height ratio, decreased sitting/standing height ratio, and increased hand length. These data suggest that the increased height in Sotos syndrome is predominantly the result of an increase in limb length [Agwu et al 1999, de Boer et al 2005].Major Features Behavioral problems. A wide range of behavioral problems are common at all ages: autistic spectrum disorder, phobias, and aggression have been described [Tatton-Brown, personal communication]. Often difficulty with peer group relationships is precipitated by large size, naiveté, and lack of awareness of social cues [Finegan et al 1994]. These observations were confirmed in a study of individuals with a clinical diagnosis of Sotos syndrome (some with and some without an NSD1 mutation); it was additionally noted that attention-deficit hyperactivity disorder (ADHD) is not common among individuals with Sotos syndrome [de Boer et al 2006] Bone age. Bone age often reflects the accelerated growth velocity and is advanced in 75%-80% of prepubertal children. However, bone age interpretation is influenced by the "threshold" taken as significant, the method of assessment, subjective interpretative error, and the age at which the assessment is made. Cardiac abnormalities. About 20% of individuals have cardiac anomalies that range in severity from single, often self-limiting anomalies including PDA, ASD, and VSD to more severe, complex cardiac abnormalities. Recently two unrelated individuals with Sotos syndrome were shown to have left ventricular non-compaction [Martinez et al 2011]. Only a minority of the cardiac abnormalities associated with Sotos syndrome require surgical intervention.Cranial MRI/CT abnormalities are identified in the majority of individuals with Sotos syndrome and an NSD1 mutation. Ventricular dilatation (particularly in the trigone region) is most frequently identified, but other abnormalities include midline changes (hypoplasia or agenesis of the corpus callosum, mega cisterna magna, cavum septum pellucidum), cerebral atrophy, and small cerebellar vermis [Waggoner et al 2005]. Dental abnormalities. Premature dental eruption and poor dental quality have been reported [Cole & Hughes 1994, Leventopoulos et al 2009].Joint hyperlaxity/pes planus. Joint laxity is reported in at least 20% of individuals with Sotos syndrome. Pregnancy. Complications in pregnancy may occur. In particular, maternal preeclampsia occurs in about 15% of pregnancies of children with Sotos syndrome. Neonatal complications. Neonates may have jaundice (~65%), hypotonia (~75%), and poor feeding (~70%). These complications tend to resolve spontaneously, but in a small minority intervention is required. Renal abnormalities. About 15% of individuals with an NSD1 mutation have a renal abnormality; vesicoureteric reflux is the most common. Some individuals may have quiescent vesicoureteric reflux and may present in adulthood with renal impairment. Scoliosis. Present in about 30% of affected individuals, scoliosis is only rarely severe enough to require bracing or surgery. Seizures. Approximately 25% of individuals with Sotos syndrome develop non-febrile seizures at some point in their lives and some require ongoing therapy. Absence, tonic-clonic, myoclonic, and partial complex seizures have all been reported. Other Tumors. Tumors occur in approximately 3% of persons with Sotos syndrome and include sacrococcygeal teratoma, neuroblastoma, presacral ganglioma, acute lymphoblastic leukemia (ALL) and small cell lung cancer [Hersh et al 1992, Tatton-Brown & Rahman 2004]. De Boer and colleagues have characterized and reviewed these problems and compared persons with Sotos syndrome who have NSD1 mutations to those who do not [de Boer et al 2006]. Various other clinical features have been associated with Sotos syndrome. Some associated features, such as constipation and hearing problems caused by chronic otitis media, are common. If future studies show that some associated features occur in more than 15% of individuals with Sotos syndrome and therefore at higher frequencies than in the general population, these features may be secondary to disruption of NSD1 rather than incidental findings. The following features are seen in 2%-15% of individuals with Sotos syndrome [Tatton-Brown et al 2005b]: AstigmatismCataract Cholesteatoma Conductive hearing loss Constipation Contractures Craniosynostosis Cryptorchidism Gastroesophageal reflux Hemangioma HemihypertrophyHydrocele Hypercalcemia Hypermetropia Hypodontia Hypoplastic nailsHypospadias Hypothyroidism Inguinal hernia Myopia Neonatal hypoglycemiaNystagmusPectus excavatum PhimosisSkin hyperpigmentationSkin hypopigmentationStrabismusTalipes equinovarusTumors Umbilical hernia Vertebral anomalies 2/3 toe syndactyly

Genotype-Phenotype CorrelationsThrough evaluation of 234 individuals with Sotos syndrome with an NSD1 abnormality, it has been shown that, in general, individuals with a 5q35 microdeletion have less overgrowth and more severe learning disability than individuals with an intragenic mutation [Tatton-Brown et al 2005b].Genotype-phenotype correlations are not evident between intragenic mutations and 5q35 microdeletions for other clinical features associated with Sotos syndrome (i.e., cardiac abnormalities, renal anomalies, seizures, scoliosis). In addition, no correlations were observed between type of intragenic mutation (missense vs truncating) and phenotype or between position of mutation (5' vs 3') and phenotype [Tatton-Brown et al 2005b].

Differential DiagnosisOvergrowth conditions that may be confused with Sotos syndrome: Weaver syndrome (also known as Weaver-Smith syndrome). Weaver syndrome has recently been shown to be caused by mutations within the histone methyltransferase, EZH2 [Tatton-Brown et al 2011, Gibson et al 2012]. Affected individuals are tall, have a typical, but subtle, facial appearance, are frequently hypertonic at birth, and often have associated joint problems such as camptodactyly and contractures. The classic facial appearance overlaps with that of Sotos syndrome, particularly in infancy. However, the face in Weaver syndrome is round in shape with ocular hypertelorism. Prognathism is not a feature, but the chin appears "stuck on" and, frequently, a horizontal crease is present between the chin and lower lip. Because of the clinical overlap between Weaver syndrome and Sotos syndrome, NSD1 testing should be considered if an EZH2 mutation is not identified. Beckwith-Wiedemann syndrome (BWS). Individuals with BWS typically have height and weight at least 2 SD above the mean; macrosomia is a major diagnostic criterion. However, many of the other findings in BWS, including macroglossia, anterior ear lobe creases/helical pits, omphalocele, and visceromegaly, are not evident in Sotos syndrome. Molecular genetic testing can identify epigenetic and genomic alterations of chromosome 11p15 in individuals with BWS: (1) loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals; (2) paternal uniparental disomy for chromosome 11p15 in 20%; and (3) gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Sequence analysis of CDKN1C identifies mutations in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS.
Of note, although Baujat et al [2004] reported NSD1 mutations in two individuals with BWS, the individuals do not fulfill the diagnostic criteria for BWS and do fulfill the diagnostic criteria for Sotos syndrome (see Genetically Related Disorders). BWS should be distinguishable from Sotos syndrome clinically. Molecular testing for both conditions is indicated in individuals with clinical overlap. Simpson-Golabi-Behmel syndrome (SGBS). This X-linked condition is also associated with pre- and postnatal overgrowth in males. However, other features of SGBS not typically found in Sotos syndrome include polydactyly, supernumerary nipples, diastasis recti, and pectus excavatum. The facial gestalt also differs between the two disorders. Microdeletions and mutations of GPC3 encoding the protein glypican 3 are causative. Bannayan-Riley-Ruvalcaba syndrome. This autosomal dominant condition is characterized by macrocephaly, vascular malformations, hamartomatous polyps of the distal ileum and colon, pigmented macules on the shaft of the penis, lipomas, and increased risk of thyroid and breast cancer. Mutations of PTEN have been found in about 60% of cases. A somewhat similar facial gestalt in combination with overgrowth may lead to confusion with Sotos syndrome, but a detailed clinical examination and molecular genetic testing should differentiate the two conditions. Benign familial macrocephaly. This autosomal dominant condition is characterized by dolico- or macrocephaly in an individual who is otherwise neurologically normal. It is likely a heterogeneous condition and is usually a diagnosis of exclusion. Fragile X syndrome. Similarities may exist between fragile X syndrome and Sotos syndrome. However, the two conditions are usually distinguishable on clinical grounds; molecular testing confirms the diagnosis.Nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas usually from the third decade onwards. Most individuals have skeletal anomalies such as bifid ribs or wedge-shaped vertebrae. About 60% of individuals have a recognizable appearance with macrocephaly, bossing of the forehead, and coarse facial features. Head circumference increases above the 98th centile until age ten to 18 months, but is not usually associated with global developmental delay. NBCCS is caused by germline mutations in PTCH. Inheritance is autosomal dominant. Chromosomal abnormalities. A Sotos syndrome-like phenotype has been associated with 4p duplications, mosaic 20p trisomy [Faivre et al 2000], and 22q13.3 deletion syndrome. Karyotyping should identify these chromosome abnormalities. Nonspecific overgrowth. Many individuals with overgrowth do not fulfill the diagnostic criteria for any of the above conditions but nevertheless have other features (e.g., learning difficulties, distinctive facial features) that suggest an underlying genetic cause. Nonspecific overgrowth is likely to be a heterogeneous group of conditions with multiple causes. 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 DiagnosisTo establish the extent of disease in an individual diagnosed with Sotos syndrome, the following evaluations are recommended [Tatton-Brown & Rahman 2007]:A thorough history to identify known features/associations of the disorder: learning difficulties, cardiac and renal anomalies, seizures, and scoliosisPhysical examination including cardiac auscultation, blood pressure measurement, and back examination for scoliosis Investigations to detect abnormalities before they result in significant morbidity/mortality: In children in whom the diagnosis has just been established, echocardiogram and renal ultrasound examination In adults in whom the diagnosis has just been established, renal ultrasound examination to evaluate for renal damage from quiescent chronic vesicoureteric reflux Referral for audiologic assessment. Conductive hearing loss may occur at an increased frequency in Sotos syndrome; thus, the threshold for referral should be low. Medical genetics consultationTreatment of ManifestationsWhen clinical problems (e.g., cardiac abnormalities, seizures, renal problems, scoliosis) or difficulties with learning/behavior/speech are identified, referral to the appropriate specialist is recommended. If MRI has been performed and ventricular dilatation demonstrated, shunting should not usually be necessary as the "arrested hydrocephalus" associated with Sotos syndrome is typically non-obstructive and not associated with raised intracranial pressure. If raised intracranial pressure is suspected, investigation and management in consultation with neurologists and neurosurgeons would be appropriate. Some children in North America have been prescribed Ritalin^® with varying success; in Europe, behavioral management strategies are more commonly used, again with varying success.Prevention of Secondary Complications Antibiotic prophylaxis is indicated in individuals with proven vesicoureteric reflux.SurveillanceRegular review (by a general pediatrician) is recommended for younger children, individuals with many medical complications needing coordination of medical specialists, and families requiring more support than average [Tatton-Brown & Rahman 2007]. The clinician may wish to review less frequently older children/teenagers and those individuals without many medical complications. The following are appropriate at the clinical review: Thorough history to identify known clinical sequelae of Sotos syndrome Examination for curvature of the spine Cardiac auscultation Blood pressure measurement Referral for audiologic assessment if hearing is a concern or if the child has had many upper respiratory tract infections Referral to an ophthalmologist if strabismus or other problem with vision is suspectedUrine dipstick to assess for quiescent urine infection Referral to the appropriate clinical specialist if problems are identified Note: Cancer screening is not recommended. (1) The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [Tatton-Brown et al 2005b, Tatton-Brown & Rahman 2007]. This level of risk does not warrant routine screening, particularly as screening for neuroblastoma has not been shown to decrease mortality and can lead to false positive results [Schilling et al 2002]. (2) Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated [Scott et al 2006].Evaluation of Relatives at RiskSee 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. Note: There may not be clinical trials for this disorder.

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. Sotos Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNSD15q35​.2-q35.3Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specificNuclear receptor binding SET Domain protein 1 (NSD1) @ LOVDNSD1Data 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 Sotos Syndrome (View All in OMIM) View in own window 117550SOTOS SYNDROME 1; SOTOS1 606681NUCLEAR RECEPTOR-BINDING Su-var, ENHANCER OF ZESTE, AND TRITHORAX DOMAIN PROTEIN 1; NSD1Normal allelic variants. NSD1 comprises 22 coding exons (NM_022455.4). Many normal variants have been identified [Douglas et al 2003, Kurotaki et al 2003, Rio et al 2003, Turkmen et al 2003, Tatton-Brown et al 2005b]. Pathologic allelic variants. More than 100 pathogenic allelic variants have been published. No mutational hot spots have been identified [Douglas et al 2003, Kurotaki et al 2003, Rio et al 2003, Turkmen et al 2003, Faravelli 2005, Tatton-Brown et al 2005b]. See Table A. A recurrent 1.9-Mb 5q35 microdeletion encompassing NSD1 has been reported in most Japanese and some non-Japanese individuals with Sotos syndrome [Kurotaki et al 2003, Tatton-Brown et al 2005a, Tatton-Brown et al 2005b, Visser et al 2005]. The majority are generated by nonallelic homologous recombination between flanking low-copy repeats [Kurotaki et al 2003, Tatton-Brown et al 2005a, Visser et al 2005]. Many of these recurrent deletions have the same breakpoints, and a specific chromatin structure may increase recurrent crossover events and predispose to recombination hot spots at 5q35 [Visser et al 2005]. Normal gene product. Only limited data exist regarding the functions of histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific (NSD1), a protein of 2696 amino acids. It is expressed in the brain, kidney, skeletal muscle, spleen, thymus, and lung. NSD1 contains at least 12 functional domains including two nuclear receptor interaction domains (NID^-L and NID^+L), two proline-tryptophan-tryptophan-proline (PWWP) domains, five plant homeo domains (PHD), and a SET (su(var)3-9, enhancer of zeste, trithorax) domain. The most distinctive of these domains are the SET and associated SAC (SET-associated Cys-rich) domains, which are found in histone methyltransferases that regulate chromatin states. The SET domain of NSD1 has unique histone specificity, methylating K36 on H3 and K20 on H4 [Rayasam et al 2003]. PHDs are also typically found in proteins that act at the chromatin level, and PWWP domains are implicated in protein-protein interactions and are often found in methyltransferases. The nuclear receptors of NSD1, NID^-L, and NID^+L are typical of those found in corepressors and coactivators [Huang et al 1998]. The presence of these distinctive domains suggests that NSD1 is a histone methyltransferase that acts as a transcriptional intermediary factor capable of both negatively and positively influencing transcription, depending on the cellular context [Kurotaki et al 2001]. Abnormal gene product. How functional abrogation of NSD1 results in Sotos syndrome is not currently known.