Entry - #610253 - KLEEFSTRA SYNDROME 1; KLEFS1 - OMIM - (OMIM.ORG)

 
ICD+
# 610253

KLEEFSTRA SYNDROME 1; KLEFS1


Alternative titles; symbols

CHROMOSOME 9q34.3 DELETION SYNDROME
9q- SYNDROME
9q SUBTELOMERIC DELETION SYNDROME


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
9q34.3 Kleefstra syndrome 1 610253 AD 3 EHMT1 607001
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE - Autosomal dominant [SNOMEDCT: 263681008, 771269000] [UMLS: C1867440, C0443147 HPO: HP:0000006] [HPO: HP:0000006] GROWTH Weight - Obesity [SNOMEDCT: 414915002, 414916001] [ICD10CM: E66. 9] [ICD9CM: 278. 00] [UMLS: C0028754, C4759928 HPO: HP:0001513] [HPO: HP:0001513] HEAD & NECK Head - Brachycephaly [SNOMEDCT: 13649004] [UMLS: C0221356 HPO: HP:0000248] [HPO: HP:0000248] - Microcephaly [SNOMEDCT: 1148757008] [ICD10CM: Q02] [ICD9CM: 742. 1] [UMLS: C0025958, C4551563 HPO: HP:0000252] [HPO: HP:0000252] Face - Flat face [UMLS: C1853241 HPO: HP:0012368] [HPO: HP:0012368] - Prognathism [SNOMEDCT: 72855002, 22810007, 109504005] [ICD10CM: M26. 213] [ICD9CM: 524. 23] [UMLS: C0399526, C0033324 HPO: HP:0000303] [HPO: HP:0000303] - Midface hypoplasia [UMLS: C1853242 HPO: HP:0011800] [HPO: HP:0011800] - Coarse facies [UMLS: C1845847 HPO: HP:0000280] [HPO: HP:0000280] Ears - Malformed ears [UMLS: C0857379 HPO: HP:0000377] [HPO: HP:0000377] - Hearing loss [SNOMEDCT: 103276001, 15188001, 343087000] [ICD10CM: H91. 9] [ICD9CM: 389. 9, 389] [UMLS: C0018772, C3887873, C2029884, C0011053, C1384666 HPO: HP:0000365] [HPO: HP:0000365] Eyes - Hypertelorism [SNOMEDCT: 22006008] [ICD10CM: Q75. 2] [ICD9CM: 376. 41] [UMLS: C0020534 HPO: HP:0000316] [HPO: HP:0000316] - Synophrys [SNOMEDCT: 253207002] [UMLS: C0431447 HPO: HP:0000664] [HPO: HP:0000664] - Upslanting palpebral fissures [SNOMEDCT: 246799009] [UMLS: C0423109 HPO: HP:0000582] [HPO: HP:0000582] Nose - Anteverted nares [SNOMEDCT: 708670007] [UMLS: C1840077 HPO: HP:0000463] [HPO: HP:0000463] Mouth - Carp-shaped mouth [UMLS: C1856202 HPO: HP:0010806] [HPO: HP:0010806] - Everted lower lip [SNOMEDCT: 767502001] [UMLS: C1853246 HPO: HP:0000232] [HPO: HP:0000232] - Macroglossia [SNOMEDCT: 270516002, 25273001] [ICD10CM: Q38. 2, K14. 8] [ICD9CM: 750. 15] [UMLS: C0024421, C0009677 HPO: HP:0000158] [HPO: HP:0000158] CARDIOVASCULAR Heart - Conotruncal heart defects [UMLS: C1853238 HPO: HP:0001710] [HPO: HP:0001710] SKELETAL Hands - Brachydactyly [SNOMEDCT: 43476002] [UMLS: C0221357 HPO: HP:0001156] [HPO: HP:0001156] - Single transverse palmar creases [SNOMEDCT: 248409006] [UMLS: C0424731 HPO: HP:0000954] [HPO: HP:0000954] SKIN, NAILS, & HAIR Hair - Synophrys [SNOMEDCT: 253207002] [UMLS: C0431447 HPO: HP:0000664] [HPO: HP:0000664] NEUROLOGIC Central Nervous System - Mental retardation, severe [SNOMEDCT: 40700009] [ICD10CM: F72] [ICD9CM: 318. 1] [UMLS: C0036857 HPO: HP:0010864] [HPO: HP:0010864] - Hypotonia [SNOMEDCT: 398152000, 398151007] [UMLS: C0026827, C1858120 HPO: HP:0001290, HP:0001252] [HPO: HP:0001252] - Seizures [SNOMEDCT: 91175000] [UMLS: C0036572 HPO: HP:0001250] [HPO: HP:0001250] Behavioral Psychiatric Manifestations - Behavioral problems [SNOMEDCT: 277843001] [UMLS: C5886745 HPO: HP:0000708] [HPO: HP:0000708] - Sleep disorders [SNOMEDCT: 39898005] [ICD10CM: G47. 9, G47] [UMLS: C0851578] - Obsessive-compulsive disorder [SNOMEDCT: 191736004, 12479006] [ICD10CM: F42. 8, F42. 9, R46. 81, F42] [ICD9CM: 300 V体育官网. 3] [UMLS: C0028768, C0600104 HPO: HP:0000722] [HPO: HP:0000722] - Stereotypic movements [UMLS: C1853236] [HPO: HP:0000733] - Aggressive behavior [SNOMEDCT: 61372001] [UMLS: C0001807 HPO: HP:0000718] [HPO: HP:0000718] MISCELLANEOUS - De novo mutation in most cases - Many cases have submicroscopic subtelomeric deletions of chromosome 9q leading to haploinsufficiency of EHMT1 (607001) MOLECULAR BASIS - Caused by mutation in the euchromatic histone methyltransferase-1 gene (EHMT1, 607001. 0001) ▲ Close Intellectual developmental disorder, autosomal dominant - PS156200 - 65 Entries Location Phenotype Inheritance Phenotypemapping key PhenotypeMIM number Gene/Locus Gene/LocusMIM number 1p36. 11 Coffin-Siris syndrome 2 AD 3 614607 ARID1A 603024 1q21. 3 White-Sutton syndrome AD 3 616364 POGZ 614787 1q21. 3 GAND syndrome AD 3 615074 GATAD2B 614998 1q22 Intellectual developmental disorder, autosomal dominant 52 AD 3 617796 ASH1L 607999 1q25. 3 Intellectual developmental disorder, autosomal dominant 75 AD 3 620988 DHX9 603115 1q44 Intellectual developmental disorder, autosomal dominant 22 AD 3 612337 ZBTB18 608433 2p25. 3 Intellectual developmental disorder, autosomal dominant 39 AD 3 616521 MYT1L 613084 2q11. 2 . Intellectual developmental disorder, autosomal dominant 69 AD 3 617863 LMAN2L 609552 2q23. 1 Intellectual developmental disorder, autosomal dominant 1 AD 3 156200 MBD5 611472 3p25. 3 Intellectual developmental disorder, autosomal dominant 23 AD 3 615761 SETD5 615743 3p21. 31 Intellectual developmental disorder, autosomal dominant 70 AD 3 620157 SETD2 612778 3q22. 3 Intellectual developmental disorder, autosomal dominant 47 AD 3 617635 STAG1 604358 3q26. 32 Intellectual developmental disorder, autosomal dominant 41 AD 3 616944 TBL1XR1 608628 3q27. 1 Intellectual developmental disorder 60 with seizures AD 3 618587 AP2M1 601024 4q31. 1 Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities AD 3 617787 NAA15 608000 5p15. 2 Intellectual developmental disorder, autosomal dominant 44, with microcephaly AD 3 617061 TRIO 601893 5p15. 2 Intellectual developmental disorder, autosomal dominant 63, with macrocephaly AD 3 618825 TRIO 601893 5q13. 3 Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies AD 3 616351 CERT1 604677 5q32 Intellectual developmental disorder, autosomal dominant 53 AD 3 617798 CAMK2A 114078 5q33. 2 Intellectual developmental disorder, autosomal dominant 67 AD 3 619927 GRIA1 138248 6p21. 32 Intellectual developmental disorder, autosomal dominant 5 AD 3 612621 SYNGAP1 603384 6q13 Intellectual developmental disorder, autosomal dominant 46 AD 3 617601 KCNQ5 607357 6q14. 3 Intellectual developmental disorder, autosomal dominant 64 AD 3 619188 ZNF292 616213 6q22. 1 Intellectual developmental disorder, autosomal dominant 55, with seizures AD 3 617831 NUS1 610463 6q24. 2 Intellectual developmental disorder, autosomal dominant 43 AD 3 616977 HIVEP2 143054 6q25. 3 Coffin-Siris syndrome 1 AD 3 135900 ARID1B 614556 7p22. 1 Intellectual developmental disorder, autosomal dominant 48 AD 3 617751 RAC1 602048 7p13 Intellectual developmental disorder, autosomal dominant 54 AD 3 617799 CAMK2B 607707 7q11. 22 Intellectual developmental disorder, autosomal dominant 26 AD 3 615834 AUTS2 607270 7q36. 1 Kleefstra syndrome 2 AD 3 617768 KMT2C 606833 7q36. 2 Intellectual developmental disorder, autosomal dominant 33 AD 3 616311 DPP6 126141 9p24 Intellectual developmental disorder, autosomal dominant 2 AD 4 614113 MRD2 614113 9q34. 11 Intellectual developmental disorder, autosomal dominant 58 AD 3 618106 SET 600960 9q34. 3 Kleefstra syndrome 1 AD 3 610253 EHMT1 607001 10p15. 3 Intellectual developmental disorder, autosomal dominant 30 AD 3 616083 ZMYND11 608668 10q22. 2 Intellectual developmental disorder, autosomal dominant 59 AD 3 618522 CAMK2G 602123 11p15. 5 Vulto-van Silfout-de Vries syndrome AD 3 615828 DEAF1 602635 11q13. 1 Intellectual developmental disorder, autosomal dominant 76 AD 3 621285 MARK2 600526 11q13. 1-q13. 2 Schuurs-Hoeijmakers syndrome AD 3 615009 PACS1 607492 11q13. 2 Intellectual developmental disorder, autosomal dominant 51 AD 3 617788 KMT5B 610881 11q24. 2 Intellectual developmental disorder, autosomal dominant 4 AD 2 612581 MRD4 612581 12p13. 1 Intellectual developmental disorder, autosomal dominant 6, with or without seizures AD 3 613970 GRIN2B 138252 12q13. 12 Intellectual developmental disorder, autosomal dominant, FRA12A type AD 3 136630 DIP2B 611379 12q21. 33 Intellectual developmental disorder, autosomal dominant 66 AD 3 619910 ATP2B1 108731 14q11. 2 Intellectual developmental disorder, autosomal dominant 74 AD 3 620688 HNRNPC 164020 15q21. 3 Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities AD 3 620330 RFX7 612660 16p13. 3 Intellectual developmental disorder, autosomal dominant 72 AD 3 620439 SRRM2 606032 16q22. 1 Intellectual developmental disorder, autosomal dominant 21 AD 3 615502 CTCF 604167 16q24. 3 Intellectual developmental disorder, autosomal dominant 3 AD 3 612580 CDH15 114019 17p13. 1 Intellectual developmental disorder, autosomal dominant 62 AD 3 618793 DLG4 602887 17q21. 31 Koolen-De Vries syndrome AD 3 610443 KANSL1 612452 17q23. 1 Intellectual developmental disorder, autosomal dominant 56 AD 3 617854 CLTC 118955 17q23. 2 Intellectual developmental disorder, autosomal dominant 61 AD 3 618009 MED13 603808 17q23. 2 Intellectual developmental disorder, autosomal dominant 57 AD 3 618050 TLK2 608439 18q12. 3 Intellectual developmental disorder, autosomal dominant 29 AD 3 616078 SETBP1 611060 19p13. 3 Intellectual developmental disorder, autosomal dominant 65 AD 3 619320 KDM4B 609765 19p13. 2 Coffin-Siris syndrome 4 AD 3 614609 SMARCA4 603254 19q13. 12 Intellectual developmental disorder, autosomal dominant 68 AD 3 619934 KMT2B 606834 19q13. 2 Intellectual developmental disorder, autosomal dominant 45 AD 3 617600 CIC 612082 20q11. 23 . Intellectual developmental disorder, autosomal dominant 11 AD 3 614257 EPB41L1 602879 20q13. 33 Intellectual developmental disorder, autosomal dominant 73 AD 3 620450 TAF4 601796 20q13. 33 Intellectual developmental disorder, autosomal dominant 38 AD 3 616393 EEF1A2 602959 21q22. 13 Intellectual developmental disorder, autosomal dominant 7 AD 3 614104 DYRK1A 600855 22q11. 23 Coffin-Siris syndrome 3 AD 3 614608 SMARCB1 601607 22q12. 3 . Intellectual developmental disorder, autosomal dominant 10 AD 3 614256 CACNG2 602911 Kleefstra syndrome - PS610253 - 2 Entries Location Phenotype Inheritance Phenotypemapping key PhenotypeMIM number Gene/Locus Gene/LocusMIM number 7q36. 1 Kleefstra syndrome 2 AD 3 617768 KMT2C 606833 9q34. 3 Kleefstra syndrome 1 AD 3 610253 EHMT1 607001 ▲ Close ▼ TEXT A number sign (#) is used with this entry because of evidence that Kleefstra syndrome-1 (KLEFS1) is caused by heterozygous mutation in the EHMT1 gene (607001), which is located within the region of the chromosome 9q34. 3 deletion syndrome.


▼ Description

Submicroscopic subtelomeric deletions of chromosome 9q are associated with a recognizable intellectual developmental syndrome. Common features in patients with 9q subtelomeric deletion syndrome are severely impaired intellectual development, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects (Harada et al. , 2004; Iwakoshi et al. , 2004; Stewart et al VSports手机版. , 2004; Neas et al. , 2005). .

Genetic Heterogeneity of Kleefstra Syndrome

KLEFS2 (617768) is caused by mutation in the KMT2C gene (606833) on chromosome 7q36.

▼ Clinical Features

Kleefstra et al. (2009) reported 16 patients with 9q deletions identified by routine chromosome testing or whole genome array analysis and 6 additional patients with intragenic EHMT1 mutations and normal chromosome studies. All patients showed the core phenotype of the deletion syndrome, including mental retardation without speech development, hypotonia, and characteristic facial features. Facial features included microcephaly, brachycephaly, hypertelorism, synophrys, midface hypoplasia, protruding tongue, eversion of the lower lip, and prognathism. Birth weight was often increased compared to normal and many had childhood obesity. Motor function was delayed, but all individuals were able to walk between 2 and 3 years, except 1 patient. Eight patients had congenital heart defects, including atrial or ventricular septal defects, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis V体育ios版. Seven patients had seizures. Less common and variable features included micropenis, cryptorchidism, vesicoureteral reflux, tracheo-/bronchomalacia, and gastroesophageal reflux. Brain imaging was generally normal, but some showed dilated ventricles, abnormal myelination, or other mild changes. Five patients that reached adult age showed abrupt behavioral changes around adolescence with some later recovery. Abnormalities included apathy, aggressive periods, psychosis, autistic features, catatonia, bipolar mood disorder, and regression in daily function and cognitive abilities. There were no apparent genotype/phenotype correlations with the size of the deletion or between those with deletions and those with mutations. Kleefstra et al. (2009) concluded that haploinsufficiency for the EHMT1 gene is responsible for the main phenotypic features. .

Verhoeven et al. (2011) reviewed the clinical histories of 3 unrelated women, aged 43, 33, and 19 years, with Kleefstra syndrome. Two had a heterozygous intragenic loss-of-function mutation in the EHMT1 gene and the third had a heterozygous 9q34. 3 microdeletion encompassing the EHMT1 gene. All had delayed psychomotor development since early childhood, and showed progressive regression in behavior. The oldest patient showed a decline in global functioning beginning at age 38 years and necessitating institutionalization. The other 2 patients showed onset of behavioral regression around puberty. On physical examination as adults, all showed the characteristic facial features of Kleefstra syndrome, as well as rigid flexion of the arms, legs, hands, and feet and slow motor functioning. Abnormal behaviors included impulsivity, poor speech, repetitive behaviors, restricted social interactions, apathy, and poor response to external stimuli. All were severely disabled. The 2 older patients showed signs of catatonia, and both had white matter abnormalities on brain imaging VSports最新版本. All patients had a disturbed sleep-wake pattern. The findings were consistent with a neurodegenerative or regressive neurologic process. .

▼ Inheritance

Most cases of Kleefstra syndrome are caused by de novo mutations. However, Willemsen et al. (2011) reported 2 unrelated families in which affected children inherited an interstitial 9q34. 3 deletion from a mildly affected mother who was somatically mosaic for the deletion. Features in the 2 mothers included learning difficulties and mild facial dysmorphisms such as hypoplastic midface, upslanting palpebral fissures, depressed nasal root, and anteverted nares. The first family carried a 233-kb deletion with a proximal breakpoint in intron 4 of the EHMT1 gene and a distal breakpoint in the CACNA1B gene (601012). The second family carried a 179- to 210-kb deletion with a proximal breakpoint upstream of the EHMT1 gene and eliminating at least 5 exons of the EHMT1 gene. Willemsen et al. (2011) noted the implications for genetic counseling and emphasized that multiplex ligation-dependent probe amplification (MLPA) may be necessary to detect mosaicism. V体育平台登录.

▼ Cytogenetics

Although the phenotype of this recognizable entity was considered to be a contiguous gene deletion syndrome, evidence indicated that the core phenotype was due to haploinsufficiency of one gene, EHMT1, which encodes chromatin histone methyltransferase-1 (607001). Kleefstra et al VSports注册入口. (2006) characterized the breakpoints in a female with a balanced translocation t(X;9)(p11. 23;q34. 3) and found that the chromosome 9 breakpoint disrupted the EHMT1 gene in intron 9. The patient presented typical features of 9q subtelomeric deletion syndrome, including severe mental retardation, facial dysmorphism, cardiac anomaly, seizures, hearing loss, and behavioral problems. .

Kleefstra et al. (2009) examined the deletion sizes in 16 patients found to have 9q deletions by routine subtelomeric chromosome testing. Initially, 7 patients were identified by FISH, 7 by multiplex ligation-dependent probe amplification (MLPA), and 2 by microarray analysis. The deletion breakpoints and sizes were heterogeneous: the most common deletion, found in 6 patients, ranged from 700 kb to 1. 3 Mb. The largest deletion was 3. 1 Mb and extended from the CACNA1B gene (601012) to the OLFM1 gene (605366). The smallest deletion was 40 kb, comprising exons 11 to 25 of the EHMT1 gene, exclusively. The patient with the largest deletion had several congenital abnormalities, such as micropenis, undescended testes, vesicoureteral reflux, and aortic coarctation, but the authors noted that these features have also been observed in patients with smaller deletions. V体育官网入口.

▼ Molecular Genetics

Kleefstra et al. (2006) identified 2 heterozygous de novo mutations, a nonsense mutation and a frameshift mutation, in the EHMT1 gene in patients with a typical 9q- phenotype (607001. 0001-607001 VSports在线直播. 0002). Of the 5 patients they reported, Kleefstra et al. (2006) remarked that the 2 with mutations were as severely affected as the 3 with deletions, and the patients with a typical 9q deletion were as severely affected as those described in the literature. .

In 6 of 24 patients with a clinical phenotype consistent with 9q deletion syndrome who had normal chromosome studies, Kleefstra et al. (2009) identified 6 different intragenic mutations in the EHMT1 gene (e. g. , C1042Y, 607001. 0003; R260X, 607001. 0004). There were 2 nonsense mutations, a deletion, 2 splice site mutations, and 1 missense mutation at a highly conserved residue V体育2025版. A comparison of the phenotype between these 6 patients and 16 additional patients with larger deletions of 9q showed no genotype/phenotype correlations. Kleefstra et al. (2009) concluded that haploinsufficiency for EHMT1 is the basis for the phenotypic features in this disorder. .

Yatsenko et al. (2009) characterized genomic rearrangements in 28 unrelated patients with 9q34. 3 subtelomeric deletions. Four distinct categories were delineated: terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Each kind results in haploinsufficiency of the EHMT1 gene and a characteristic phenotype. Seven (25%) patients had de novo interstitial deletions, 7 (25%) were found with derivative chromosomes or complex rearrangements, and 14 (50%) had bona fide terminal deletions. Interspersed repetitive elements (including Alu, LINE, LTR, and STR) were frequently observed at the breakpoints. Repetitive elements may play an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes or assist in either DNA double-strand break repair or repair of single double-strand DNA ends generated by collapsed forks VSports. Sequence analysis of the breakpoint junctions suggested that subtelomeric deletions may be stabilized by both homologous and nonhomologous recombination mechanisms, through a telomere-capture event, de novo telomere synthesis, or multistep breakage-fusion-bridge cycles. .

Genetic Heterogeneity

Among 4 of 9 EHMT1 mutation-negative patients with core phenotypic features of Kleefstra syndrome but with phenotypic heterogeneity, referred to as Kleefstra syndrome spectrum (KSS), 22726846, images] [Full Text]" pmid="22726846">Kleefstra et al. (2012) identified de novo mutations in 4 genes, MBD5 (611472), MLL3 (606833), SMARCB1 (601607), and NR1I3 (603881), that encode epigenetic regulators. Shared phenotypic features among these patients include intellectual disability and childhood hypotonia, present in all, and behavioral problems, synophrys, and midface hypoplasia, present in a majority. Otherwise the phenotypes were quite variable. Using Drosophila, 22726846, images] [Full Text]" pmid="22726846">Kleefstra et al. (2012) demonstrated that MBD5, MLL3, and NR1I3, cooperate with EHMT1; SMARCB1 was known to interact directly with MLL3.


▼ REFERENCES

  1. Harada, N., Visser, R., Dawson, A., Fukamachi, M., Iwakoshi, M., Okamoto, N., Kishino, T., Niikawa, N., Matsumoto, N. A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome. J. Hum. Genet. 49: 440-444, 2004. [PubMed: 15258833, related citations] [Full Text]

  2. Iwakoshi, M., Okamoto, N., Harada, N., Nakamura, T., Yamamori, S., Fujita, H., Niikawa, N., Matsumoto, N. 9q34.3 deletion syndrome in three unrelated children. Am. J. Med. Genet. 126A: 278-283, 2004. [PubMed: 15054842, related citations] [Full Text]

  3. Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A., Genevieve, D., Cormier-Daire, V., van Esch, H., Fryns, J.-P., Hamel, B. C. J., Sistermans, E. A., de Vries, B. B. A., van Bokhoven, H. Loss-of-function mutations in Euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am. J. Hum. Genet. 79: 370-377, 2006. [PubMed: 16826528, images, related citations] [Full Text]

  4. Kleefstra, T., Kramer, J. M., Neveling, K., Willemsen, M. H., Koemans, T. S., Vissers, L. E. L. M., Wissink-Lindhout, W., Fenckova, M., van den Akker, W. M. R., Nadif Kasri, N., Nillesen, W. M., Prescott, T., and 10 others. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91: 73-82, 2012. [PubMed: 22726846, images, related citations] [Full Text]

  5. Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V., Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., Wilson, M., McGaughran, J., and 16 others. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J. Med. Genet. 46: 598-606, 2009. [PubMed: 19264732, related citations] [Full Text]

  6. Neas, K. R., Smith, J. M., Chia, N., Huseyin, S., St. Heaps, L., Peters, G., Sholler, G., Tzioumi, D., Sillence, D. O., Mowat, D. Three patients with terminal deletions within the subtelomeric region of chromosome 9q. Am. J. Med. Genet. 132A: 425-430, 2005. [PubMed: 15633179, related citations] [Full Text]

  7. Stewart, D. R., Huang, A., Faravelli, F., Anderlid, B.-M., Medne, L., Ciprero, K., Kaur, M., Rossi, E., Tenconi, R., Nordenskjold, M., Gripp, K. W., Nicholson, L., and 12 others. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. Am. J. Med. Genet. 128A: 340-351, 2004. [PubMed: 15264279, related citations] [Full Text]

  8. Verhoeven, W. M. A., Egger, J. I. M., Vermeulen, K., van de Warrenburg, B. P. C., Kleefstra, T. Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. Am. J. Med. Genet. 155A: 2409-2415, 2011. [PubMed: 21910222, related citations] [Full Text]

  9. Willemsen, M. H., Beunders, G., Callaghan, M., de Leeuw, N., Nillesen, W. M., Yntema, H. G., van Hagen, J. M., Nieuwint, A. W., Morrison, N., Keijzers-Vloet, S. T., Hoischen, A., Brunner, H. G., Tolmie, J., Kleefstra, T. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clin. Genet. 80: 31-38, 2011. [PubMed: 21204793, related citations] [Full Text]

  10. Yatsenko, S. A., Brundage, E. K., Roney, E. K., Cheung, S. W., Chinault, A. C., Lupski, J. R. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum. Molec. Genet. 18: 1924-1936, 2009. [PubMed: 19293338, images, related citations] [Full Text]


Contributors:
Ada Hamosh - updated : 11/26/2013
Cassandra L. Kniffin - updated : 9/5/2012
Cassandra L. Kniffin - updated : 8/15/2011
George E. Tiller - updated : 2/24/2010
Cassandra L. Kniffin - updated : 12/29/2009
Creation Date:
Victor A. McKusick : 7/13/2006
Edit History:
carol : 11/21/2024
carol : 10/02/2024
carol : 11/14/2017
ckniffin : 11/10/2017
alopez : 10/05/2016
alopez : 11/26/2013
carol : 9/6/2012
ckniffin : 9/5/2012
alopez : 8/18/2011
ckniffin : 8/15/2011
wwang : 2/25/2010
terry : 2/24/2010
carol : 2/24/2010
carol : 1/8/2010
ckniffin : 12/29/2009
carol : 10/29/2008
carol : 9/17/2008
terry : 8/25/2006
alopez : 7/13/2006

VSports app下载 - # 610253

KLEEFSTRA SYNDROME 1; KLEFS1


Alternative titles; symbols

CHROMOSOME 9q34.3 DELETION SYNDROME
9q- SYNDROME
9q SUBTELOMERIC DELETION SYNDROME


ICD10CM: Q87.86;   ORPHA: 261494, 261652, 96147;   DO: 0060352;   MONDO: 0027407;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
9q34.3 Kleefstra syndrome 1 610253 Autosomal dominant 3 EHMT1 607001

TEXT

A number sign (#) is used with this entry because of evidence that Kleefstra syndrome-1 (KLEFS1) is caused by heterozygous mutation in the EHMT1 gene (607001), which is located within the region of the chromosome 9q34.3 deletion syndrome.

Description

Submicroscopic subtelomeric deletions of chromosome 9q are associated with a recognizable intellectual developmental syndrome. Common features in patients with 9q subtelomeric deletion syndrome are severely impaired intellectual development, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects (Harada et al., 2004; Iwakoshi et al., 2004; Stewart et al., 2004; Neas et al., 2005).

Genetic Heterogeneity of Kleefstra Syndrome

KLEFS2 (617768) is caused by mutation in the KMT2C gene (606833) on chromosome 7q36.

Clinical Features

Kleefstra et al. (2009) reported 16 patients with 9q deletions identified by routine chromosome testing or whole genome array analysis and 6 additional patients with intragenic EHMT1 mutations and normal chromosome studies. All patients showed the core phenotype of the deletion syndrome, including mental retardation without speech development, hypotonia, and characteristic facial features. Facial features included microcephaly, brachycephaly, hypertelorism, synophrys, midface hypoplasia, protruding tongue, eversion of the lower lip, and prognathism. Birth weight was often increased compared to normal and many had childhood obesity. Motor function was delayed, but all individuals were able to walk between 2 and 3 years, except 1 patient. Eight patients had congenital heart defects, including atrial or ventricular septal defects, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis. Seven patients had seizures. Less common and variable features included micropenis, cryptorchidism, vesicoureteral reflux, tracheo-/bronchomalacia, and gastroesophageal reflux. Brain imaging was generally normal, but some showed dilated ventricles, abnormal myelination, or other mild changes. Five patients that reached adult age showed abrupt behavioral changes around adolescence with some later recovery. Abnormalities included apathy, aggressive periods, psychosis, autistic features, catatonia, bipolar mood disorder, and regression in daily function and cognitive abilities. There were no apparent genotype/phenotype correlations with the size of the deletion or between those with deletions and those with mutations. Kleefstra et al. (2009) concluded that haploinsufficiency for the EHMT1 gene is responsible for the main phenotypic features.

Verhoeven et al. (2011) reviewed the clinical histories of 3 unrelated women, aged 43, 33, and 19 years, with Kleefstra syndrome. Two had a heterozygous intragenic loss-of-function mutation in the EHMT1 gene and the third had a heterozygous 9q34.3 microdeletion encompassing the EHMT1 gene. All had delayed psychomotor development since early childhood, and showed progressive regression in behavior. The oldest patient showed a decline in global functioning beginning at age 38 years and necessitating institutionalization. The other 2 patients showed onset of behavioral regression around puberty. On physical examination as adults, all showed the characteristic facial features of Kleefstra syndrome, as well as rigid flexion of the arms, legs, hands, and feet and slow motor functioning. Abnormal behaviors included impulsivity, poor speech, repetitive behaviors, restricted social interactions, apathy, and poor response to external stimuli. All were severely disabled. The 2 older patients showed signs of catatonia, and both had white matter abnormalities on brain imaging. All patients had a disturbed sleep-wake pattern. The findings were consistent with a neurodegenerative or regressive neurologic process.


Inheritance

Most cases of Kleefstra syndrome are caused by de novo mutations. However, Willemsen et al. (2011) reported 2 unrelated families in which affected children inherited an interstitial 9q34.3 deletion from a mildly affected mother who was somatically mosaic for the deletion. Features in the 2 mothers included learning difficulties and mild facial dysmorphisms such as hypoplastic midface, upslanting palpebral fissures, depressed nasal root, and anteverted nares. The first family carried a 233-kb deletion with a proximal breakpoint in intron 4 of the EHMT1 gene and a distal breakpoint in the CACNA1B gene (601012). The second family carried a 179- to 210-kb deletion with a proximal breakpoint upstream of the EHMT1 gene and eliminating at least 5 exons of the EHMT1 gene. Willemsen et al. (2011) noted the implications for genetic counseling and emphasized that multiplex ligation-dependent probe amplification (MLPA) may be necessary to detect mosaicism.


Cytogenetics

Although the phenotype of this recognizable entity was considered to be a contiguous gene deletion syndrome, evidence indicated that the core phenotype was due to haploinsufficiency of one gene, EHMT1, which encodes chromatin histone methyltransferase-1 (607001). Kleefstra et al. (2006) characterized the breakpoints in a female with a balanced translocation t(X;9)(p11.23;q34.3) and found that the chromosome 9 breakpoint disrupted the EHMT1 gene in intron 9. The patient presented typical features of 9q subtelomeric deletion syndrome, including severe mental retardation, facial dysmorphism, cardiac anomaly, seizures, hearing loss, and behavioral problems.

Kleefstra et al. (2009) examined the deletion sizes in 16 patients found to have 9q deletions by routine subtelomeric chromosome testing. Initially, 7 patients were identified by FISH, 7 by multiplex ligation-dependent probe amplification (MLPA), and 2 by microarray analysis. The deletion breakpoints and sizes were heterogeneous: the most common deletion, found in 6 patients, ranged from 700 kb to 1.3 Mb. The largest deletion was 3.1 Mb and extended from the CACNA1B gene (601012) to the OLFM1 gene (605366). The smallest deletion was 40 kb, comprising exons 11 to 25 of the EHMT1 gene, exclusively. The patient with the largest deletion had several congenital abnormalities, such as micropenis, undescended testes, vesicoureteral reflux, and aortic coarctation, but the authors noted that these features have also been observed in patients with smaller deletions.


Molecular Genetics

Kleefstra et al. (2006) identified 2 heterozygous de novo mutations, a nonsense mutation and a frameshift mutation, in the EHMT1 gene in patients with a typical 9q- phenotype (607001.0001-607001.0002). Of the 5 patients they reported, Kleefstra et al. (2006) remarked that the 2 with mutations were as severely affected as the 3 with deletions, and the patients with a typical 9q deletion were as severely affected as those described in the literature.

In 6 of 24 patients with a clinical phenotype consistent with 9q deletion syndrome who had normal chromosome studies, Kleefstra et al. (2009) identified 6 different intragenic mutations in the EHMT1 gene (e.g., C1042Y, 607001.0003; R260X, 607001.0004). There were 2 nonsense mutations, a deletion, 2 splice site mutations, and 1 missense mutation at a highly conserved residue. A comparison of the phenotype between these 6 patients and 16 additional patients with larger deletions of 9q showed no genotype/phenotype correlations. Kleefstra et al. (2009) concluded that haploinsufficiency for EHMT1 is the basis for the phenotypic features in this disorder.

Yatsenko et al. (2009) characterized genomic rearrangements in 28 unrelated patients with 9q34.3 subtelomeric deletions. Four distinct categories were delineated: terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Each kind results in haploinsufficiency of the EHMT1 gene and a characteristic phenotype. Seven (25%) patients had de novo interstitial deletions, 7 (25%) were found with derivative chromosomes or complex rearrangements, and 14 (50%) had bona fide terminal deletions. Interspersed repetitive elements (including Alu, LINE, LTR, and STR) were frequently observed at the breakpoints. Repetitive elements may play an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes or assist in either DNA double-strand break repair or repair of single double-strand DNA ends generated by collapsed forks. Sequence analysis of the breakpoint junctions suggested that subtelomeric deletions may be stabilized by both homologous and nonhomologous recombination mechanisms, through a telomere-capture event, de novo telomere synthesis, or multistep breakage-fusion-bridge cycles.

Genetic Heterogeneity

Among 4 of 9 EHMT1 mutation-negative patients with core phenotypic features of Kleefstra syndrome but with phenotypic heterogeneity, referred to as Kleefstra syndrome spectrum (KSS), Kleefstra et al. (2012) identified de novo mutations in 4 genes, MBD5 (611472), MLL3 (606833), SMARCB1 (601607), and NR1I3 (603881), that encode epigenetic regulators. Shared phenotypic features among these patients include intellectual disability and childhood hypotonia, present in all, and behavioral problems, synophrys, and midface hypoplasia, present in a majority. Otherwise the phenotypes were quite variable. Using Drosophila, Kleefstra et al. (2012) demonstrated that MBD5, MLL3, and NR1I3, cooperate with EHMT1; SMARCB1 was known to interact directly with MLL3.


REFERENCES

  1. Harada, N., Visser, R., Dawson, A., Fukamachi, M., Iwakoshi, M., Okamoto, N., Kishino, T., Niikawa, N., Matsumoto, N. A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome. J. Hum. Genet. 49: 440-444, 2004. [PubMed: 15258833] [Full Text: https://doi.org/10.1007/s10038-004-0166-z]

  2. Iwakoshi, M., Okamoto, N., Harada, N., Nakamura, T., Yamamori, S., Fujita, H., Niikawa, N., Matsumoto, N. 9q34.3 deletion syndrome in three unrelated children. Am. J. Med. Genet. 126A: 278-283, 2004. [PubMed: 15054842] [Full Text: https://doi.org/10.1002/ajmg.a.20602]

  3. Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A., Genevieve, D., Cormier-Daire, V., van Esch, H., Fryns, J.-P., Hamel, B. C. J., Sistermans, E. A., de Vries, B. B. A., van Bokhoven, H. Loss-of-function mutations in Euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am. J. Hum. Genet. 79: 370-377, 2006. [PubMed: 16826528] [Full Text: https://doi.org/10.1086/505693]

  4. Kleefstra, T., Kramer, J. M., Neveling, K., Willemsen, M. H., Koemans, T. S., Vissers, L. E. L. M., Wissink-Lindhout, W., Fenckova, M., van den Akker, W. M. R., Nadif Kasri, N., Nillesen, W. M., Prescott, T., and 10 others. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91: 73-82, 2012. [PubMed: 22726846] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.003]

  5. Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V., Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., Wilson, M., McGaughran, J., and 16 others. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J. Med. Genet. 46: 598-606, 2009. [PubMed: 19264732] [Full Text: https://doi.org/10.1136/jmg.2008.062950]

  6. Neas, K. R., Smith, J. M., Chia, N., Huseyin, S., St. Heaps, L., Peters, G., Sholler, G., Tzioumi, D., Sillence, D. O., Mowat, D. Three patients with terminal deletions within the subtelomeric region of chromosome 9q. Am. J. Med. Genet. 132A: 425-430, 2005. [PubMed: 15633179] [Full Text: https://doi.org/10.1002/ajmg.a.30496]

  7. Stewart, D. R., Huang, A., Faravelli, F., Anderlid, B.-M., Medne, L., Ciprero, K., Kaur, M., Rossi, E., Tenconi, R., Nordenskjold, M., Gripp, K. W., Nicholson, L., and 12 others. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. Am. J. Med. Genet. 128A: 340-351, 2004. [PubMed: 15264279] [Full Text: https://doi.org/10.1002/ajmg.a.30136]

  8. Verhoeven, W. M. A., Egger, J. I. M., Vermeulen, K., van de Warrenburg, B. P. C., Kleefstra, T. Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. Am. J. Med. Genet. 155A: 2409-2415, 2011. [PubMed: 21910222] [Full Text: https://doi.org/10.1002/ajmg.a.34186]

  9. Willemsen, M. H., Beunders, G., Callaghan, M., de Leeuw, N., Nillesen, W. M., Yntema, H. G., van Hagen, J. M., Nieuwint, A. W., Morrison, N., Keijzers-Vloet, S. T., Hoischen, A., Brunner, H. G., Tolmie, J., Kleefstra, T. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clin. Genet. 80: 31-38, 2011. [PubMed: 21204793] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01607.x]

  10. Yatsenko, S. A., Brundage, E. K., Roney, E. K., Cheung, S. W., Chinault, A. C., Lupski, J. R. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum. Molec. Genet. 18: 1924-1936, 2009. [PubMed: 19293338] [Full Text: https://doi.org/10.1093/hmg/ddp114]


Contributors:
Ada Hamosh - updated : 11/26/2013
Cassandra L. Kniffin - updated : 9/5/2012
Cassandra L. Kniffin - updated : 8/15/2011
George E. Tiller - updated : 2/24/2010
Cassandra L. Kniffin - updated : 12/29/2009

Creation Date:
Victor A. McKusick : 7/13/2006

Edit History:
carol : 11/21/2024
carol : 10/02/2024
carol : 11/14/2017
ckniffin : 11/10/2017
alopez : 10/05/2016
alopez : 11/26/2013
carol : 9/6/2012
ckniffin : 9/5/2012
alopez : 8/18/2011
ckniffin : 8/15/2011
wwang : 2/25/2010
terry : 2/24/2010
carol : 2/24/2010
carol : 1/8/2010
ckniffin : 12/29/2009
carol : 10/29/2008
carol : 9/17/2008
terry : 8/25/2006
alopez : 7/13/2006



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
Printed: Oct. 28, 2025