• 1
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
HMGA2 (HGNC:5009) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
high mobility group AT-hook 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
HMGIC
Alias symbols
BABL, LIPO
%HI
1.82(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.87(Read more about gnomAD pLI score)
LOEUF
0.45(Read more about gnomAD LOEUF score)
Cytoband
12q14.3
Genomic Coordinates
GRCh37/hg19: chr12:66218240-66360071 NCBI Ensembl UCSC
GRCh38/hg38: chr12:65824460-65966291 NCBI Ensembl UCSC
MANE Select Transcript
NM_003483.6 ENST00000403681.7 (Read more about MANE Select)
Function
Functions as a transcriptional regulator. Functions in cell cycle regulation through CCNA2. Plays an important role in chromosome condensation during the meiotic G2/M transition of spermatocytes. Plays a role in postnatal myogenesis, is involved in satellite cell activation (By similarity). Positively regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner (PubMed:28796236). {ECO:0000250|UniProtKB:P52927, ECO:0000269|PubMed:14645522, ECO:0000269|PubMed:28796236}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-562
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/14/2021

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 21803798
    Del Blanco DG et al., (2011) reported a heterozygous 20 bp deletion in the intronic region of HMGA2 (NM_003483.4 c.250-29_-9del) 9 bp before the start of exon 4 from a cohort of 69 patients presenting with IGHD (isolated growth hormone deficiency). This variant was absent in the databases and healthy controls. This variant was not present in the phenotypically normal mother and two siblings of the patient. The relative gene expression level determined from an average of triplicate real-time PCR experiments from fibroblast cDNA showed a decreased expression of the isoforms HMGA2d and HMGA2e in the patient compared with the control. This is the first report of a deletion in the HMGA2 gene that might be related to IGHD.
  • PUBMED: 25809938
    De Crescenzo A et al., (2015) reported a 7 bp intronic deletion in the HMGA2 gene in two individuals of a three generation family with the clinical characteristics of Silver-Russell Syndrome (SRS). Two other family members (grandmother and maternal aunt) presented with the same phenotype but did not have genetic testing. The variant was absent in 50 normal controls and not reported in the mutation databases. Haploinsufficiency of HMGA2 was demonstrated using minigene system and transient transfection experiments. This report suggested HMGA2 pathogenic variants leading to haploinsufficiency might be a rare cause of SRS.
  • PUBMED: 29655892
    Leszinski GS et al., (2018) reported a de novo heterozygous 7.3 kb deletion on chromosome 12q14.3 including exon 1 and 2 of HMGA2 in a 4-year-old female patient with the clinical diagnosis of SRS and negative results in common genetic SRS diagnostics by Whole exome sequencing. HMGA2 encodes an architectural transcription factor. This proband presented prenatal and postnatal growth retardation. Both parents were of normal height as well as her two siblings.
  • PUBMED: 28796236
    Habib WA et al., (2018) reported a de novo nonsense variant in the HMGA2 gene (NM_003483.4:c.193C>T) leading to premature termination (NP_003474.1:p.Gln65*) and a deletion of a single nucleotide (NM_003483.4:c.189delC) leading to an elongated protein (NP_003474.1:p.Ala64Leufs*102) in two sporadic female cases of Intrauterine growth retardation (IUGR) and a diagnosis of SRS via whole-exome sequencing, then verified by standard Sanger sequencing. For the de novo variant, parental inheritance was verified using short tandem repeat typing on chromosome 14 (D14S65 and D14S292). In the latter case, the origin of this deletion could not be investigated due to lack of parental DNA but the father’s adult height of 155 cm strongly suggesting that he passed this deletion to his son.
  • PUBMED: 32421827
    Hubner CT et al., (2020) reported a heterozygous deletion of exons 1 to 3 of the HMGA2 gene (NM_003483.4) in a 2-year-old German patient and his likewise affected father, and a de novo heterozygous HMGA2 splice-site variant in a 4-year-old boy from Lithuania (NM_003483.4:c.111+1G>T; Chr12(GRCh38):g.65825382G>T). They also reported a homozygous missense variant in exon 3 of HMGA2 (NM_003483.4:c.239C>T; p.Pro80Leu; Chr12(GRCh37):g.66232339C>T) in 2 siblings with severe short stature by WES. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. This variant (NM_003483.4:c.239C>T; p.Pro80Leu) in a homozygous state was also reported later by Meyer R et al., in 2021 (PMID: 33482836). The “pigmy” phenotype in HMGA2 homozygous and heterozygous mice with a decreased body size of 25% and 60%, respectively was observed.
  • PUBMED: 33482836
    Meyer R et al., (2021) reported a de novo heterozygous splicing variant NM_003483.4:c.111+1G>T(p.?) in a female and homozygous missense variants (NM_003483.4:c.239C >T p.Pro80Leu) in two siblings, boy and girl, by whole exome sequencing. The missense variant is inherited from their parents. All these three cases had clinical diagnosis of SRS. The variant (NM_003483.4:c.239C >T p.Pro80Leu) in the homozygous state was also reported in 2020 (PMID: 32421827).
HI Evidence Comments:
The high mobility AT hook 2 (HMGA2) gene is small non-histone proteins family of architectural transcription factors. Expression of HMGA2 is repressed in normal adult cells, but it is high in cells during embryogenesis. It can bind DNA in the minor groove of B-form DNA and modify the chromatin conformational state and its accessibility by several regulatory factors, involved in the modulation of gene expression. Copy number loss and variants leading to haploinsufficiency have been reported in patients with SRS (Silver-Russell syndrome) or SRS like phenotypes. Copy number variants and point mutations of the HMGA2 gene in a group of patients affected by syndromic and non-syndromic pre/postnatal growth retardation. Generally, patients with an HMGA2 haploinsufficiency had proportionate short stature. In the human, chromosome aberrations leading to gain-of-function of HMGA2 are associated with overgrowth and mesenchymal tumors (Ligon AH et al., 2005. PMID: 15593017.) while a common SNP in HMGA2 is associated with height variation in the general population (Weedon MN et al., 2007. PMID: 17767157.). Haploinsufficiency of HMGA2 is believed to be responsible for the growth retardation of the 12q14 microdeletion syndrome, while triplosensitivity of this gene has not been represented in literature. Additional Evidence: PMID: 30753492 Plachy L et al., (2019) reported a likely pathogenic heterozygous missense variant (c.223C.T p.Arg75Trp) by WES examination in a child with growth hormone deficiency (GHD) and short stature. This variant is present the affected mother. PMID: 33729509 Vishnopolska SA et al., (2021) identified the same heterozygous missense variant (HMGA2:c.223C>T, p.Arg75Trp) in a patient present with IGHD, and short stature from a cohort of 170 Argentinean patients diagnosed with IGHD (isolated GH deficiency) or CPHD (combined pituitary hormone deficiency) belonging to 168 unrelated families. This missense variant effects the 3rd AT-hook motif, is absent in control population databases, and this position is highly conserved. Arginine to tryptophan variants are usually highly disruptive. This supports the idea of a role of HMGA2 in the IGHD etiology. PMID: 29501611 Heldt F et al., (2018) reported the first family with short stature and Silver-Russell like phenotype due to a microdeletion in 12q14.3. The heterozygous loss of 1.67 MB in the index patient and the other two affected family members includes the genes HMGA2, LLPH, TMBIM4, IRAK3, HELB, GRIP1, and the pseudogene RPSAP52. this report concluded from these results and from the data of other patients reported in the literature that haploinsufficiency of HMGA2 leads to the short stature in this family. PMID 22987822 Fischetto R et al., (2017) reported a second family of three members of severe short stature carries the 12q14 microdeletion. The deletion revealed a 1.9 Mb heterozygous 12q14.2q14.3 deletion (arr-[hg19]12q14.2q14.3(64,636,776 × 2,64,638,433–66,555,663 × 1,66,555,756 × 2) encompassing 14 genes and 3 miRNAs including HMGA2 gene. This author summarized 15 other cases previously reported carrying a 12q14 overlapping deletion and predicts the HMGA2 is the main candidate gene for growth retardation although deletion of some other genes, like XPOT, TBK1, and WIF1, might be possible candidate genes in the etiology of the phenotypes. PMID: 19298872 Buysse K et al., (2009) reported the 12q14 microdeletion in two patients. The author reviewed other 5 patient reported in literature. This author emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes including MGHA2 gene despite variable breakpoints. This report provided evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this syndrome. PMID: 22987822 Alyaoub F et al., (2012) reported a deletion of 4.17-4.21 Mb containing 25 RefSeq genes including including IRAK3, GRIP1, and the 3' portion of the HMGA2 gene. This article provides additional supports for the role of the HMGA1 gene in human growth. PMID: 3272336 Mercadante F et al., (2020) a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene in a 3-year-old male patient with clinical diagnosis of Silver-Russell Syndrome (SRS) and reviewed all previously known patients with mutations of the HMGA2 gene or deletions of 12q14.3 involving this gene. The author suggested investigation of HMGA2 gene in all the patients with evocative phenotype for SRS and negative genetic results for MS-MLPA at the imprinting region 11p15 and microsatellite markers of chromosome 7. PMID: 22140081 Bibb AL et al., (2012) reported a mother and daughter with short stature, microcephaly, learning disabilities, and mild dysmorphic features, both of whom have the same 12q14 microdeletion. This author reviewed 7 sporadic cases of this deletion reported. All of whom have the so called 12q14 microdeletion syndrome which contains other genes in addition to HMGA2 gene. It appears that the deletion of these six genes is sufficient to cause the 12q14 microdeletion syndrome. It was concluded the short stature seen in our patients and others with 12q14 microdeletions possibly is caused by haploinsufficiency of the HMGA2 gene which is also supported by the fact that deletion of this gene causes a mouse pygmy phenotype. PMID: 22887875 Takenouchi T et al., (2012) reported 4Mb deletion at 12q14.3–q15 from position 64366496 to 68348402 (NCBI36/hg18) involving HMGA2 gene in a Japanese girl suggestive of clinical diagnosis of SRS including the short stature with severe IUGR and short fifth fingers, but without macrocephaly. The haploinsufficiency of HMGA2 contributes to the short stature phenotype was proposed, while the haploinsufficiency of a gene residing centromeric to HMGA2 contributes to the macrocephaly phenotype.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 31900140
    Dória et al., (2020) reported a 1.5 Mb reciprocal microduplication of the 12q14 deletion syndrome in a girl presenting overgrowth and obesity. It was suggested a phenotypically recognizable 12q14 microduplication syndrome and the role of HMGA2 gene in growth regulation. This finding does not exclude other genes, such as IRAK3 and MSRB3 in the role of weight gain and obesity.

Genomic View

Select assembly: (NC_000012.11) (NC_000012.12)