ORPHA: 96125; DO: 0060422; MONDO: 0012948;
Cytogenetic location: 6pter-p24 Genomic coordinates (GRCh38) : 6:1-13,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6pter-p24 | Chromosome 6pter-p24 deletion syndrome | 612582 | Isolated cases | 4 |
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.
See also Axenfeld-Rieger syndrome type 3 (RIEG3; 602482), which shows phenotypic overlap with chromosome 6pter-p24 deletion syndrome, and branchiooculofacial syndrome (BOFS; 113620), caused by mutation or deletion of the TFAP2A gene (107580) on chromosome 6p24.3, centromeric to the deletion interval.
Davies et al. (1999) reported 6 patients with interstitial or terminal 6pter-p24 deletions. All patients had developmental delay and hypotonia, and most had an abnormal skull shape, such as brachycephaly, dolichocephaly, or frontal bossing. Variable features included downslanting palpebral fissures, midface hypoplasia, anterior eye chamber abnormalities (see RIEG3, 602482), ear anomalies, hearing loss, heart defects, and a short neck.
Mirza et al. (2004) reported 6 additional patients with developmental delay and hypotonia associated with deletions involving chromosome 6pter-p24 region. Common clinical features included hypertelorism, structural eye defects, anterior eye chamber abnormalities, palatal and dental abnormalities, hearing loss, congenital heart defects, neuronal defects, and anomalies of the extremities. Less common features included structural ear and nose anomalies, and kidney defects. Mirza et al. (2004) suggested that the FOXC1 (601090) was likely involved in the eye anomalies.
Lin et al. (2005) reported 4 patients with a distinct recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, tented mouth, Dandy-Walker malformation/variant (see 220210), congenital heart defects, anterior eye-chamber abnormalities, hearing loss, hypotonia, and developmental delay. All were found to have terminal deletions involving the chromosome 6pter-p24 and -p25 chromosomal segment.
DeScipio et al. (2005) reported 6 children from 3 families with subtelomeric deletions of chromosome 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy-Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There was considerable phenotypic overlap with 3C syndrome (220210).
Maclean et al. (2005) stated that 12 cases had been reported of a distinctive clinical phenotype associated with deletion of distal chromosome 6p, the features of which included Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. They reported the case of a child in whom recognition of the specific ocular and facial phenotype led to identification of a 6p microdeletion arising from a de novo 6;18 translocation. Detailed analysis confirmed deletion of the FOXC1, FOXF2 (603250), and FOXQ1 (612788) forkhead gene cluster at chromosome 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delays. Unlike previous reports, hearing was normal.
Martinet et al. (2008) reported 2 unrelated patients with de novo subtelomeric terminal deletion of chromosome 6p. An 8-month-old girl had dysmorphic facial features, including broad forehead, hypertelorism, downslanting palpebral fissures, midface hypoplasia, dysplastic ears and short neck, with severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. A 5-year-old male born with unilateral hip dysplasia had the characteristic facial phenotype, high-arched palate with abnormal tooth position, bilateral posterior embryotoxon, atrial septal defect, and moderate mental retardation. High-resolution array comparative genomic hybridization (CGH) showed that the girl had an 8.1-Mb deletion of chromosome 6pter-p24.3 associated with a contiguous 5.8-Mb duplication of chromosome 6p24.3-p24.1. The boy had a 5.7-Mb deletion of 6pter-p25.1 partially overlapping that of the first patient.
Kuipers et al. (2013) reported 2 patients with overlapping de novo interstitial 1.4-Mb deletions that included chromosome 6p25.1-p24.3, containing 6 genes: RREB1 (602209), NRN1 (607409), CAGE1 (608304), LY86 (605241), SSR1 (600868), and F13A1 (134570). Patient 1 had weight loss and difficulty with temperature regulation in the first week of life. Developmental delay was present at 1 year of age. She had an atrial septal defect, and she had frequent infections in the first year of life. At 17 months of age, she had dysmorphic features including a prominent forehead, flat facies, downslanting almond-shaped eyes, epicanthal folds, and low-set ears. She also had complete cutaneous syndactyly of digits 3 and 4 of the left hand, clinodactyly of the 5th fingers and toes, and partial bilateral cutaneous syndactyly of the 2nd and 3rd toes. She also had brittle, sparse hair and cutis marmorata. SNP array identified a de novo 3.8-Mb deletion at chromosome 6p25.2-p24.3 and a de novo 2.45-Mb deletion at chromosome 1p22.3-p22.2. Patient 2 had hypotonia and motor developmental delay at 10 months of age. At 3 years of age, he had a prominent forehead, almond-shaped eyes with everted lower lids, low-set ears, and microretrognathia. He also had long fingers and toes, bilateral 4th and 5th finger clinodactyly, mild joint hyperlaxity, sparse stiff hair, and a hemangioma. SNP array showed a de novo 2.9-Mb deletion at chromosome 6p25.1-p24.3
Qi et al. (2015) reported a patient with a 5.6-Mb interstitial deletion at chromosome 6p25.1-p24.3 identified by CGH array. She had a hemangioma on her neck noted at 1 week of age and a patent foramen ovale diagnosed at 12 months of age. At 26 months of age she had dysmorphic features, speech delay, and mild growth delay. At 3 years and 9 months of age she was noted to have a high anterior hairline, upslanting palpebral fissures, synophrys, hypertelorism, and a broad nasal bridge. She also had mild hearing loss and a pectus excavatum.
Kent et al. (2020) reported a patient with a de novo chromosome 6p25.1-p24.3 deletion detected by chromosome array. He had an inguinal hernia repair at 1 month of age and was diagnosed with failure to thrive at 9 months of age. He had multiple respiratory infections in childhood and was diagnosed with IgA deficiency. He developed seizures at 6 years of age, and a brain MRI showed possible gliosis adjacent to the left ventricle. On evaluation at 8 years of age, he had proportionate short stature, a tall and broad forehead, low-set ears, and hypertelorism.
By molecular and cytogenetic mapping of the 6p deletions in 3 families, DeScipio et al. (2005) delineated a 1.3-Mb minimally deleted common critical region. Molecular analysis excluded mutations in the FOXC1, FOXF2, and FOXQ1 genes. Of note, DeScipio et al. (2005) did not identify deletions of 6p in 7 additional unrelated patients with 3C syndrome.
Qi et al. (2015) reported a patient with a 5.6-Mb interstitial deletion at chromosome 6p25.1-p24.3 identified on CGH array. CGH array showed that her mother had mosaicism for the chromosome 6p25.1-p24.3 deletion, and her healthy brother had a duplication at this same region. Further investigation with fluorescence in situ hybridization of the mother's cells showed that she had 3 different cell populations: 72% had the 6p25.1-p24.3 deletion, 6% had a duplication of this region, and 22% were normal. Qi et al. (2015) hypothesized that the interstitial deletion and its reciprocal duplication could occur through mitotic unequal sister chromatid exchange, and that both the deletion and duplication were passed to the offspring due to gonadal mosaicism.
Kent et al. (2020) reported a new patient and reviewed 7 published patients and 7 patients reported in the ClinVar database with chromosome 6p interstitial microdeletions encompassing chromosome 6p25.1-p24.3. The patients had clinical features consistent with a Noonan (see 163950)-spectrum disorder, including short stature, dysmorphic facial features, and cardiovascular abnormalities. Kent et al. (2020) found that the common deleted region in these patients contained the RREB gene. RREB gene expression was decreased in lymphoblastoid cells (LCLs) from the newly reported patient. The patient-derived LCLs also had increased phosphorylated MEK (see 176872) and ERK (see 601795) when stimulated with FBS and had increased proliferation compared to control cells, consistent with abnormal RAS-MAPK pathway activity.
Aldinger et al. (2009) analyzed brain imaging studies in 18 individuals with chromosome 6p25 copy number variation involving the FOXC1 gene and 3 patients with intragenic mutations of FOXC1, all of whom had previously been reported by Pearce et al. (1982, 1983); Gould et al. (1997); Mears et al. (1998); Nishimura et al. (1998); Lehmann et al. (2000); DeScipio et al. (2005); Lin et al. (2005); Maclean et al. (2005); and Chanda et al. (2008), with phenotypes of anterior segment dysgenesis (ASGD3; 601631), Axenfeld-Rieger syndrome type 3 (RIEG3; 602482), cardiac malformations, and/or brain anomalies, particularly Dandy-Walker malformation. All of the patients had abnormalities on MRI, showing classic or mild Dandy-Walker malformation (DWM), mega cisterna magna (MCM), or cerebellar vermis hypoplasia (CVH). The combined genotype and phenotype data showed consistently more severe phenotypes among individuals with large compared to small deletions, suggesting contributions from more than 1 causative gene in the region; in addition, all 12 deletions involved the FOXC1 gene plus at least 2 exons of the GMDS gene (602884), implicating one or both of these genes as having a previously unrecognized role in cerebellar development. In 3 patients from 2 families with missense mutations in FOXC1 resulting in Axenfeld anomaly (601090.0003) and Axenfeld-Rieger syndrome type 3 (601090.0008), respectively, Aldinger et al. (2009) observed mild CVH and an abnormal white matter signal corresponding to prominent perivascular spaces; the authors concluded that alteration of FOXC1 function alone can cause CVH and contributes to MCM and DWM.
Aldinger, K. A., Lehmann, O. J., Hudgins, L., Chizhikov, V. V., Bassuk, A. G., Ades, L. C., Krantz, I. D., Dobyns, W. B., Millen, K. J. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nature Genet. 41: 1037-1042, 2009. [PubMed: 19668217] [Full Text: https://doi.org/10.1038/ng.422]
Chanda, B., Asai-Coakwell, M., Ye, M., Mungall, A. J., Barrow, M., Dobyns, W. B., Behesti, H., Sowden, J. C., Carter, N. P., Walter, M. A., Lehmann, O. J. A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation. Hum. Molec. Genet. 17: 3446-3458, 2008. [PubMed: 18694899] [Full Text: https://doi.org/10.1093/hmg/ddn238]
Davies, A. F., Mirza, G., Sekhon, G., Turnpenny, P., Leroy, F., Speleman, F., Law, C., van Regemorter, N., Vamos, E., Flinter, F., Ragoussis, J. Delineation of two distinct 6p deletion syndromes. Hum. Genet. 104: 64-72, 1999. [PubMed: 10071194] [Full Text: https://doi.org/10.1007/s004390050911]
DeScipio, C., Schneider, L., Young, T. L., Wasserman, N., Yaeger, D., Lu, F., Wheeler, P. G., Williams, M. S., Bason, L., Jukofsky, L., Menon, A., Geschwindt, R., Chudley, A. E., Saraiva, J., Schinzel, A. A. G. L., Guichet, A., Dobyns, W. E., Toutain, A., Spinner, N. B., Krantz, I. D. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am. J. Med. Genet. 134A: 3-11, 2005. [PubMed: 15704124] [Full Text: https://doi.org/10.1002/ajmg.a.30573]
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Kent, O. A., Saha, M., Coyaud, E., Burston, H. E., Law, N., Dadson, K., Chen, S., Laurent, E. M., St-Germain, J., Sun, R. X., Matsumoto, Y., Cowen, J., and 10 others. Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. Nature Commun. 11: 4673, 2020. [PubMed: 32938917] [Full Text: https://doi.org/10.1038/s41467-020-18483-9]
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Qi, Z., Jeng, L. J. B., Slavotinek, A., Yu, J. Haploinsufficiency and triploinsensitivity of the same 6p25.1p24.3 region in a family. BMC Med. Genomics 8: 38, 2015. [PubMed: 26174853] [Full Text: https://doi.org/10.1186/s12920-015-0113-1]