Locus HFG HOXA13-III

Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects¹.

Prevalence

Extremely rare, published cases generally European ancestry or unknown^2,3,4.

Age of Onset

0 (birth)

HPO Terms

HP:0000010 Recurrent urinary tract infections HP:0000011 Neurogenic bladder HP:0000013 Hypoplasia of the uterus HP:0000041 Chordee HP:0000047 Hypospadias HP:0000048 Bifid scrotum HP:0000054 Micropenis HP:0000074 Ureteropelvic junction obstruction HP:0000076 Vesicoureteral reflux HP:0000083 Renal insufficiency HP:0000126 Hydronephrosis HP:0000130 Abnormality of the uterus HP:0000486 Strabismus HP:0000787 Kidney stone HP:0000795 Abnormality of the urethra HP:0000807 Glanular hypospadias HP:0000808 Penoscrotal hypospadias HP:0000813 Bicornuate uterus HP:0000960 Sacral dimple HP:0001032 Absent distal interphalangeal creases HP:0001081 Cholelithiasis HP:0001162 Postaxial hand polydactyly HP:0001216 Delayed ossification of carpal bones HP:0001241 Capitate-hamate fusion HP:0001245 Small thenar eminence HP:0001629 Ventricular septal defect HP:0001762 Talipes equinovarus HP:0001763 Pes planus HP:0001773 Short foot HP:0001792 Small nail HP:0001798 Anonychia HP:0001799 Short nail HP:0001822 Hallux valgus HP:0001857 Short distal phalanx of toe HP:0001885 Short 2nd toe HP:0002019 Constipation HP:0002144 Tethered cord HP:0003259 Elevated circulating creatinine concentration HP:0003762 Uterus didelphys HP:0004180 Short distal phalanx of the 3rd finger HP:0004209 Clinodactyly of the 5th finger HP:0004220 Short middle phalanx of the 5th finger HP:0004243 Abnormal scaphoid morphology HP:0005048 Synostosis of carpal bones HP:0006110 Shortening of all middle phalanges of the fingers HP:0007477 Abnormal dermatoglyphics HP:0008080 Hallux varus HP:0008103 Delayed tarsal ossification HP:0008111 Broad distal hallux HP:0008368 Tarsal synostosis HP:0008551 Microtia HP:0008740 Longitudinal vaginal septum HP:0009237 Short 5th finger HP:0009246 Aplasia of the distal phalanx of the 5th finger HP:0009290 Short distal phalanx of the 4th finger HP:0009464 Ulnar deviation of the 2nd finger HP:0009566 Short distal phalanx of the 2nd finger HP:0009623 Proximal placement of thumb HP:0009702 Carpal synostosis HP:0009778 Short thumb HP:0009882 Short distal phalanx of finger HP:0010034 Short 1st metacarpal HP:0010055 Broad hallux HP:0010086 Broad proximal phalanx of the hallux HP:0010103 Short distal phalanx of hallux HP:0010105 Short first metatarsal HP:0010109 Short hallux HP:0010584 Pseudoepiphyses HP:0011937 Hypoplastic fifth toenail HP:0012330 Pyelonephritis HP:0012386 Absent hallux HP:0012704 Widened subarachnoid space HP:0025633 Abnormal ureter morphology HP:0030084 Clinodactyly HP:0040025 Clinodactyly of the 4th finger HP:0100329 Tarsometatarsal synostosis HP:0100341 Tibial deviation of the 4th toe HP:0100343 Tibial deviation of the 3rd toe HP:0100347 Tibial deviation of the 5th toe HP:0100499 Tibial deviation of toes HP:0200055 Small hand HP:6000184 Filum terminale lipoma HP:6000414 Duplicate uterine cervix

Association

Mendelian

Locus

hg19 chr7:27239297-27239351

hg38 chr7:27199678-27199732

t2t chr7:27335684-27335720

Details

Anticipation does not occur, and expansions appear fully penetrant; it is unknown if contractions also lead to phenotypic variation⁴.

Mechanism

LoF

Polyalanine expansions leading to haploinsufficiency⁴.

Detection

PCR amplification of tract III, followed by fragment analysis or Sanger sequencing, has detected and sized these alleles. Standard short-read sequencing may miss expanded repeats⁴.

Year

2000⁵

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

GCN

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

NGC

Pathogen. (gene)

GCN

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007698

Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model.

Jeffrey W,Innis, Douglas,Mortlock, Zhi,Chen, Michael,Ludwig, Melissa E,Williams, Thomas M,Williams, Colleen D,Doyle, Zhihong,Shao, Michael,Glynn, Davor,Mikulic, Katarina,Lehmann, Stefan,Mundlos, Boris,Utsch

Human molecular genetics · 2004-09-22

pmid:15385446

Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome.

Boris,Utsch, Colleen D,McCabe, Kenneth,Galbraith, Ricardo,Gonzalez, Mark,Born, Jörg,Dötsch, Michael,Ludwig, Heiko,Reutter, Jeffrey W,Innis

American journal of medical genetics. Part A · 2007-12-15

pmid:17935235

Hand-Foot-Genital Syndrome

Jeffrey W.,Innis

GeneReviews® · 1993-01-01

genereviews:NBK1423

Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome.

F R,Goodman, C,Bacchelli, A F,Brady, L A,Brueton, J P,Fryns, D P,Mortlock, J W,Innis, L B,Holmes, A E,Donnenfeld, M,Feingold, F A,Beemer, R C,Hennekam, P J,Scambler

American journal of human genetics · 2000-06-05

pmid:10839976

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Unblending of Transcriptional Condensates in Human Repeat Expansion Disease.

Shaon,Basu, Sebastian D,Mackowiak, Henri,Niskanen, Dora,Knezevic, Vahid,Asimi, Stefanie,Grosswendt, Hylkje,Geertsema, Salaheddine,Ali, Ivana,Jerković, Helge,Ewers, Stefan,Mundlos, Alexander,Meissner, Daniel M,Ibrahim, Denes,Hnisz

Cell · 2020-05-07

pmid:32386547

Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation.

Kailey M,Owens, Shane C,Quinonez, Peedikayil E,Thomas, Catherine E,Keegan, Nanci,Lefebvre, Diane,Roulston, Christine A,Larsen, H Scott,Stadler, Jeffrey W,Innis

American journal of medical genetics. Part A · 2013-03-26

pmid:23532960

A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies.

Elisa M,Jorgensen, Jane I,Ruman, Leo,Doherty, Hugh S,Taylor

Fertility and sterility · 2009-07-09

pmid:19591980

Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13.

P,Debeer, C,Bacchelli, P J,Scambler, L,De Smet, J-P,Fryns, F R,Goodman

Journal of medical genetics · 2002-11-01

pmid:12414828

The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes.

S,Bruneau, K R,Johnson, M,Yamamoto, A,Kuroiwa, D,Duboule

Developmental biology · 2001-09-15

pmid:11543619