# 609053

FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
15q26.1 Fanconi anemia, complementation group I 609053 AR 3 FANCI 611360
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Short stature
Weight
- Low weight
Other
- Small for gestation age (<10%)
- Intrauterine growth retardation (IUGR)
HEAD & NECK
Head
- Microcephaly
Face
- Triangular face
- Fanconi facies
Ears
- Right auditory canal atresia
- Auditory canal stenosis
- Abnormal ossicles
- Hearing loss, conductive
Eyes
- Astigmatism
- Myopia
- Microphthalmia
- Optic nerve hypoplasia
- Optic nerve pallor
Neck
- Short neck
CARDIOVASCULAR
Heart
- Atrial septal defect
- Patent foramen ovale
- Ventricular septal defect
ABDOMEN
Gastrointestinal
- Duodenum atresia
GENITOURINARY
Kidneys
- Horseshoe kidney
- Hypoplastic kidneys
Ureters
- Vesicoureteral reflux
SKELETAL
Spine
- Fused cervical vertebrae
- Narrow C5 vertebra
Limbs
- Short radius
Hands
- Absent thumbs
- Dangling left thumb
- Hypoplastic thumb
- Short first metacarpal
SKIN, NAILS, & HAIR
Skin
- Cafe-au-lait spots
NEUROLOGIC
Central Nervous System
- Septooptic dysplasia
- Colpocephaly
- Agenesis of corpus callosum
- Absent septum pellucidum
- Arnold-Chiari malformation
- Developmental delay
- Small anterior pituitary gland with poorly visible stalk
ENDOCRINE FEATURES
- Growth hormone deficiency
- Hypothyroidism
- Hypothyroidism, tertiary (central)
HEMATOLOGY
- Neutropenia
MOLECULAR BASIS
- Caused by mutation in the FANCI gene (FANCI, 611360.0001)
Fanconi anemia - PS227650 - 21 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.22 ?Fanconi anemia, complementation group V AR 3 617243 MAD2L2 604094
1q32.1 Fanconi anemia, complementation group T AR 3 616435 UBE2T 610538
2p16.1 Fanconi anemia, complementation group L AR 3 614083 PHF9 608111
3p25.3 Fanconi anemia, complementation group D2 AR 3 227646 FANCD2 613984
6p21.31 Fanconi anemia, complementation group E AR 3 600901 FANCE 613976
7q36.1 ?Fanconi anemia, complementation group U AR 3 617247 XRCC2 600375
9p13.3 Fanconi anemia, complementation group G AR 3 614082 XRCC9 602956
9q22.32 Fanconi anemia, complementation group C AR 3 227645 FANCC 613899
11p14.3 Fanconi anemia, complementation group F AR 3 603467 FANCF 613897
13q13.1 Fanconi anemia, complementation group D1 AR 3 605724 BRCA2 600185
15q15.1 Fanconi anemia, complementation group R AD 3 617244 RAD51 179617
15q26.1 Fanconi anemia, complementation group I AR 3 609053 FANCI 611360
16p13.3 Fanconi anemia, complementation group P AR 3 613951 SLX4 613278
16p13.12 Fanconi anemia, complementation group Q AR 3 615272 ERCC4 133520
16p12.2 Fanconi anemia, complementation group N 3 610832 PALB2 610355
16q23.1 ?Fanconi anemia, complementation group W AR 3 617784 RFWD3 614151
16q24.3 Fanconi anemia, complementation group A AR 3 227650 FANCA 607139
17q21.31 Fanconi anemia, complementation group S AR 3 617883 BRCA1 113705
17q22 Fanconi anemia, complementation group O AR 3 613390 RAD51C 602774
17q23.2 Fanconi anemia, complementation group J 3 609054 BRIP1 605882
Xp22.2 Fanconi anemia, complementation group B XLR 3 300514 FANCB 300515

TEXT

A number sign (#) is used with this entry because Fanconi anemia complementation group I (FANCI) is caused by homozygous or compound heterozygous mutation in the FANCI gene (611360) on chromosome 15q26.


Description

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.


Clinical Features

Levitus et al. (2004) provided a tabulation of 11 genetically distinct FA subtypes. They reported 8 unrelated FA patients who were excluded from the known subtypes on the basis of phenotypic correction (complementation) or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represented a new group, termed complementation group I (FANCI). The remaining cell lines complemented group FANCI but did not complement each other, thus representing a second new group, FANCJ (609054). Both the FANCI and FANCJ cell lines were capable of forming an FA multiprotein core complex. This complex is required for activation of the FANCD2 protein (227646) by monoubiquitination, a key downstream event in the FA pathway. In FANCI cells, FANCD2 was not monoubiquitinated, indicating a defect upstream in the FA pathway, whereas in FANCJ cells, FANCD2 was monoubiquitinated, indicating a downstream defect. The results suggested that the FA pathway of genome stabilization may be controlled by at least 11 different genes, including FANCI and FANCJ.

Savage et al. (2015) reported 3 patients with molecularly confirmed FANCI who also had features of VACTERL/VACTERL-H association (see 192350, 276950, 314390). One patient (NCI-82-1) had short stature with height and weight below the 1st centile for age, microcephaly, and a small triangular face (Fanconi facies). She also had fused cervical vertebrae, atrial septal defect (ASD), ventricular septal defect (VSD), duodenal atresia, small kidneys, and absent thumbs. She had mild thrombocytopenia, and her bone marrow was hypocellular (30%) with a 47,XX,+i(1)(q10)[2]/46,XX[48] clonal abnormality. She died at age 11.5 years from complications of hematopoietic stem cell transplantation. Another patient (NCI-253-1) had hypothyroidism, marked short stature, microcephaly, and a short triangular face. She also had cervical vertebral anomaly, VSD, patent foramen ovale, horseshoe kidney, and absent thumb. Her blood counts were normal, but her bone marrow was hypocellular (40%) with normal cytogenetics. The third patient (NCI-309-1) had bilateral hypoplastic thumbs, microcephaly, congenital heart disease (ASD, VSD, and patent ductus arteriosus, all of which closed spontaneously), microcephaly, a small, triangular face, small eyes, small neck, narrow C5 vertebra, bilateral hypoplastic thumbs, absent radial pulses, Chiari malformation, and a small pituitary gland with poorly visualized pituitary stalk. She had previously undergone a bilateral ureteric reimplantation for grade three vesicoureteral reflux. She had normal stature and normal hormone function. She had mild neutropenia, and a bone marrow biopsy revealed 20 to 50% cellularity with trilineage hematopoiesis and normal cytogenetics.


Mapping

FA complementation group I results from mutations in the FANCI gene, which maps to chromosome 15q25-q26 (Dorsman et al., 2007).


Molecular Genetics

Dorsman et al. (2007) identified several mutations in the FANCI gene (e.g., 611360.0001-611360.0004) in 8 patients with FA complementation group I. Western blot analysis confirmed that functionally active FANCI protein was absent in patients with FA complementation group I. Sims et al. (2007) and Smogorzewska et al. (2007) also reported mutations in the FANCI gene in patients with FA complementation group I.


REFERENCES

  1. Deakyne, J. S., Mazin, A. V. Fanconi anemia: at the crossroads of DNA repair. Biochemistry 76: 36-48, 2011. [PubMed: 21568838, related citations] [Full Text]

  2. Dorsman, J. C., Levitus, M., Rockx, D., Rooimans, M. A., Oostra, A. B., Haitjema, A., Bakker, S. T., Steltenpool, J., Schuler, D., Mohan, S., Schindler, D., Arwert, F., Pals, G., Mathew, C. G., Waisfisz, Q., de Winter, J. P., Joenje, H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell. Oncol. 29: 211-218, 2007. [PubMed: 17452773, related citations] [Full Text]

  3. Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., Hoatlin, M. E., Waisfisz, Q., Arwert, F., de Winter, J. P., Joenje, H. Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes. Blood 103: 2498-2503, 2004. [PubMed: 14630800, related citations] [Full Text]

  4. Savage, S. A., Ballew, B. J., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, Chandrasekharappa, S. C., Ameziane, N., de Winter, J., Alter, B. P., NCI DCEG Cancer Sequencing Working Group. Novel FANCI mutations in Fanconi anemia with VACTERL association. Am. J. Med. Genet. 170A: 386-391, 2015. [PubMed: 26590883, related citations] [Full Text]

  5. Sims, A. E., Spiteri, E., Sims, R. J., III, Arita, A. G., Lach, F. P., Landers, T., Wurm, M., Freund, M., Neveling, K., Hanenberg, H., Auerbach, A. D., Huang, T. T. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nature Struct. Molec. Biol. 14: 564-567, 2007. [PubMed: 17460694, related citations] [Full Text]

  6. Smogorzewska, A., Matsuoka, S., Vinciguerra, P., McDonald, E. R., III, Hurov, K. E., Luo, J., Ballif, B. A., Gygi, S. P., Hofmann, K., D'Andrea, A. D., Elledge, S. J. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129: 289-301, 2007. [PubMed: 17412408, images, related citations] [Full Text]


Contributors:
Nara Sobreira - updated : 5/18/2016
Creation Date:
Victor A. McKusick : 11/30/2004
carol : 05/19/2016
carol : 5/18/2016
carol : 3/22/2016
carol : 3/18/2016
carol : 7/11/2011
mgross : 8/21/2007
alopez : 11/30/2004

# 609053

FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI


ORPHA: 84;   DO: 0111091;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
15q26.1 Fanconi anemia, complementation group I 609053 Autosomal recessive 3 FANCI 611360

TEXT

A number sign (#) is used with this entry because Fanconi anemia complementation group I (FANCI) is caused by homozygous or compound heterozygous mutation in the FANCI gene (611360) on chromosome 15q26.


Description

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.


Clinical Features

Levitus et al. (2004) provided a tabulation of 11 genetically distinct FA subtypes. They reported 8 unrelated FA patients who were excluded from the known subtypes on the basis of phenotypic correction (complementation) or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represented a new group, termed complementation group I (FANCI). The remaining cell lines complemented group FANCI but did not complement each other, thus representing a second new group, FANCJ (609054). Both the FANCI and FANCJ cell lines were capable of forming an FA multiprotein core complex. This complex is required for activation of the FANCD2 protein (227646) by monoubiquitination, a key downstream event in the FA pathway. In FANCI cells, FANCD2 was not monoubiquitinated, indicating a defect upstream in the FA pathway, whereas in FANCJ cells, FANCD2 was monoubiquitinated, indicating a downstream defect. The results suggested that the FA pathway of genome stabilization may be controlled by at least 11 different genes, including FANCI and FANCJ.

Savage et al. (2015) reported 3 patients with molecularly confirmed FANCI who also had features of VACTERL/VACTERL-H association (see 192350, 276950, 314390). One patient (NCI-82-1) had short stature with height and weight below the 1st centile for age, microcephaly, and a small triangular face (Fanconi facies). She also had fused cervical vertebrae, atrial septal defect (ASD), ventricular septal defect (VSD), duodenal atresia, small kidneys, and absent thumbs. She had mild thrombocytopenia, and her bone marrow was hypocellular (30%) with a 47,XX,+i(1)(q10)[2]/46,XX[48] clonal abnormality. She died at age 11.5 years from complications of hematopoietic stem cell transplantation. Another patient (NCI-253-1) had hypothyroidism, marked short stature, microcephaly, and a short triangular face. She also had cervical vertebral anomaly, VSD, patent foramen ovale, horseshoe kidney, and absent thumb. Her blood counts were normal, but her bone marrow was hypocellular (40%) with normal cytogenetics. The third patient (NCI-309-1) had bilateral hypoplastic thumbs, microcephaly, congenital heart disease (ASD, VSD, and patent ductus arteriosus, all of which closed spontaneously), microcephaly, a small, triangular face, small eyes, small neck, narrow C5 vertebra, bilateral hypoplastic thumbs, absent radial pulses, Chiari malformation, and a small pituitary gland with poorly visualized pituitary stalk. She had previously undergone a bilateral ureteric reimplantation for grade three vesicoureteral reflux. She had normal stature and normal hormone function. She had mild neutropenia, and a bone marrow biopsy revealed 20 to 50% cellularity with trilineage hematopoiesis and normal cytogenetics.


Mapping

FA complementation group I results from mutations in the FANCI gene, which maps to chromosome 15q25-q26 (Dorsman et al., 2007).


Molecular Genetics

Dorsman et al. (2007) identified several mutations in the FANCI gene (e.g., 611360.0001-611360.0004) in 8 patients with FA complementation group I. Western blot analysis confirmed that functionally active FANCI protein was absent in patients with FA complementation group I. Sims et al. (2007) and Smogorzewska et al. (2007) also reported mutations in the FANCI gene in patients with FA complementation group I.


REFERENCES

  1. Deakyne, J. S., Mazin, A. V. Fanconi anemia: at the crossroads of DNA repair. Biochemistry 76: 36-48, 2011. [PubMed: 21568838] [Full Text: https://doi.org/10.1134/s0006297911010068]

  2. Dorsman, J. C., Levitus, M., Rockx, D., Rooimans, M. A., Oostra, A. B., Haitjema, A., Bakker, S. T., Steltenpool, J., Schuler, D., Mohan, S., Schindler, D., Arwert, F., Pals, G., Mathew, C. G., Waisfisz, Q., de Winter, J. P., Joenje, H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell. Oncol. 29: 211-218, 2007. [PubMed: 17452773] [Full Text: https://doi.org/10.1155/2007/151968]

  3. Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., Hoatlin, M. E., Waisfisz, Q., Arwert, F., de Winter, J. P., Joenje, H. Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes. Blood 103: 2498-2503, 2004. [PubMed: 14630800] [Full Text: https://doi.org/10.1182/blood-2003-08-2915]

  4. Savage, S. A., Ballew, B. J., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, Chandrasekharappa, S. C., Ameziane, N., de Winter, J., Alter, B. P., NCI DCEG Cancer Sequencing Working Group. Novel FANCI mutations in Fanconi anemia with VACTERL association. Am. J. Med. Genet. 170A: 386-391, 2015. [PubMed: 26590883] [Full Text: https://doi.org/10.1002/ajmg.a.37461]

  5. Sims, A. E., Spiteri, E., Sims, R. J., III, Arita, A. G., Lach, F. P., Landers, T., Wurm, M., Freund, M., Neveling, K., Hanenberg, H., Auerbach, A. D., Huang, T. T. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nature Struct. Molec. Biol. 14: 564-567, 2007. [PubMed: 17460694] [Full Text: https://doi.org/10.1038/nsmb1252]

  6. Smogorzewska, A., Matsuoka, S., Vinciguerra, P., McDonald, E. R., III, Hurov, K. E., Luo, J., Ballif, B. A., Gygi, S. P., Hofmann, K., D'Andrea, A. D., Elledge, S. J. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129: 289-301, 2007. [PubMed: 17412408] [Full Text: https://doi.org/10.1016/j.cell.2007.03.009]


Contributors:
Nara Sobreira - updated : 5/18/2016

Creation Date:
Victor A. McKusick : 11/30/2004

Edit History:
carol : 05/19/2016
carol : 5/18/2016
carol : 3/22/2016
carol : 3/18/2016
carol : 7/11/2011
mgross : 8/21/2007
alopez : 11/30/2004