“…Following the idea of an allelic series, rare variants in HMGA2 might have a larger effect on body size. This is supported by the observation that patients with the 12q14 microdeletion syndrome show, among other features, significant short stature or even SRS phenotype when HMGA2 is included (Mari et al, 2009;Lynch et al, 2011, Heldt et al, 2018. Furthermore, it was shown that a knockout of Hmga2 in mice results in the pygmy phenotype, which is characterized by pre-and postnatal growth retardation and remarkable decrease in adipose tissue (Zhou et al, 1995).…”
Patients with Silver-Russell syndrome (SRS), a syndromic growth retardation syndrome, usually harbor an epimutation at chromosome 11p15 or a maternal uniparental disomy of chromosome 7. However, to date the genetic cause remains unknown in around 40% of SRS cases, suggesting genetic heterogeneity and involvement of other genes. We present a 4-year-old female patient with the clinical diagnosis of SRS and negative results in common genetic SRS diagnostics. Whole exome sequencing identified a de novo heterozygous 7.3 kb deletion on chromosome 12q14.3 including exon 1 and 2 of HMGA2. HMGA2 encodes an architectural transcription factor and has already been linked to body size variations in various genome-wide association studies and mouse models. Reviewing the literature, we found additional four patients with a phenotype of SRS harboring point mutations or structural variants involving HMGA2. We conclude that genetic testing of HMGA2 should be considered in routine diagnostics in patients with the suspicion of SRS.
“…Following the idea of an allelic series, rare variants in HMGA2 might have a larger effect on body size. This is supported by the observation that patients with the 12q14 microdeletion syndrome show, among other features, significant short stature or even SRS phenotype when HMGA2 is included (Mari et al, 2009;Lynch et al, 2011, Heldt et al, 2018. Furthermore, it was shown that a knockout of Hmga2 in mice results in the pygmy phenotype, which is characterized by pre-and postnatal growth retardation and remarkable decrease in adipose tissue (Zhou et al, 1995).…”
Patients with Silver-Russell syndrome (SRS), a syndromic growth retardation syndrome, usually harbor an epimutation at chromosome 11p15 or a maternal uniparental disomy of chromosome 7. However, to date the genetic cause remains unknown in around 40% of SRS cases, suggesting genetic heterogeneity and involvement of other genes. We present a 4-year-old female patient with the clinical diagnosis of SRS and negative results in common genetic SRS diagnostics. Whole exome sequencing identified a de novo heterozygous 7.3 kb deletion on chromosome 12q14.3 including exon 1 and 2 of HMGA2. HMGA2 encodes an architectural transcription factor and has already been linked to body size variations in various genome-wide association studies and mouse models. Reviewing the literature, we found additional four patients with a phenotype of SRS harboring point mutations or structural variants involving HMGA2. We conclude that genetic testing of HMGA2 should be considered in routine diagnostics in patients with the suspicion of SRS.
“…The remaining 5 cases were: a 7 bp deletion [11], a nonsense variant and a frameshift variant [10] and 2 deletions of exon 2 [12] and exons 1-2 [8]. The 23 deletions described so far range between 387 kb and 10.12 Mb, and involve other contiguous genes [9,[12][13][14][15][16][17][18][19][20][21][22][23]. Despite the variable size of these deletions, a critical region of 2.61 Mb has been identified.…”
Section: Discussionmentioning
confidence: 99%
“…A deletion with the same genomic and clinical features (size, genomic coordinates, maternal origin, clinical picture except for the absence of hyperhidrosis) have been previously described by Heldt et al in a family where it segregated along with Silver-Russell like phenotype. Even if neither Heldt nor the database DECIPHER refer to the case reported by the other, we believe it is reasonably to conclude that the deletions reported in DECIPHER and in Heldt paper are the same [ 2 , 13 ]. Fig.…”
Background: Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction and normal head circumference with consequent relative macrocephaly. Addictional findings are protruding forehead in early life, body asymmetry (of upper and lower limbs) and substantial feeding difficulties. Although several genetic mechanisms that cause the syndrome are known, more than 40% of patients with a SRSlike phenotype remain without an etiological diagnosis. In the last few years, different clinical reports have suggested that mutations or deletions of the HMGA2 gene can be responsible for a SRS-like phenotype in patients with negative results of the common diagnostic tests for this syndrome. Case presentation: We present a 3-year-old male patient with clinical diagnosis of Silver-Russell Syndrome (SRS) associated with a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene. Conclusions: Our report confirms the etiological role of HMGA2 as a disease gene in the development of a SRS-like phenotype.
“…Genes discussed in the main text or in the Supplemental Materials are indicated. Fischetto et al, 2017;Heldt et al, 2018;Mercadante et al, 2020; Figure 3, Supplementary Table 2).…”
Section: Individual 1 Fits the Spectrum Of 12q13q15 Deletions Encompassing The 12q14 Microdeletion Syndromementioning
confidence: 99%
“…Twenty-seven individuals (14 females, and 13 males) with overlapping deletions located within 12q13q15 have been previously reported with varying degrees of global developmental delay/intellectual disability, growth retardation and short stature as the main phenotype (Menten et al, 2007 ; Buysse et al, 2009 ; Mari et al, 2009 ; Spengler et al, 2010 ; Lynch et al, 2011 ; Alyaqoub et al, 2012 ; Bibb et al, 2012 ; Takenouchi et al, 2012 ; Fischetto et al, 2017 ; Heldt et al, 2018 ; Mercadante et al, 2020 ; Figure 3 , Supplementary Table 2 ).…”
Section: Literature Review Of Chromosome 12q Deletionsmentioning
Interstitial deletions on the long arm of chromosome 12 (12q deletions) are rare, and are associated with intellectual disability, developmental delay, failure to thrive and congenital anomalies. The precise genotype-phenotype correlations of different deletions has not been completely resolved. Ascertaining individuals with overlapping deletions and complex phenotypes may help to identify causative genes and improve understanding of 12q deletion syndromes. We here describe two individuals with non-overlapping 12q14 deletions encountered at our clinical genetics outpatient clinic and perform a review of all previously published interstitial 12q deletions to further delineate genotype-phenotype correlations. Both individuals presented with a neurodevelopmental disorder with various degrees of intellectual disability, failure to thrive and dysmorphic features. Previously, larger deletions overlapping large parts of the deletions encountered in both individuals have been described. Whereas, individual 1 seems to fit into the previously described phenotypic spectrum of the 12q14 microdeletion syndrome, individual 2 displays more severe neurological symptoms, which are likely caused by haploinsufficiency of the BAF complex member SMARCC2, which is included in the deletion. We furthermore perform a review of all previously published interstitial 12q deletions which we found to cluster amongst 5 regions on chromosome 12, to further delineate genotype-phenotype correlations, and we discuss likely disease relevant genes for each of these deletion clusters. Together, this expands knowledge on deletions on chromosome 12q which might facilitate patient counseling. Also, it illustrates that re-analysis of previously described microdeletions syndromes in the next generation sequencing era can be useful to delineate genotype-phenotype correlations and identify disease relevant genes in individuals with neurodevelopmental disorders.
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