Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver-Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver-Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well-recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved.     

Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13)

Behnecke A, Hinderhofer K, Jauch A, Janssen JWG, Moog U. Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13). Silver-Russell syndrome (SRS) is a genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation, typical facial features and a spectrum of additional features including body and limb asymmetry and clinodactyly. Maternal uniparental disomy for chromosome 7 (upd(7)mat) was shown to occur in 5-10% of patients with SRS. Maternal UPD7 is clinically often associated with mild SRS. Parents of an affected child are given a negligible recurrence risk as all reported cases with upd(7)mat have been sporadic so far. In general, chromosomal rearrangements-like translocations increase the likelihood of uniparental disomy (UPD) for the chromosomes involved. However, SRS as the result of a upd(7)mat in association with an inherited chromosomal translocation involving chromosome 7 has only been reported once before. Here, we describe the second case of SRS with upd(7)mat due to a familial reciprocal translocation t(7;13). This emphasizes the importance of chromosome analysis in SRS patients with upd(7)mat to rule out chromosomal rearrangements despite their rare occurrence as they are of great relevance for genetic counseling of SRS families.     

Maternal uniparental disomy 7 in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is characterised by intrauterine and postnatal growth failure accompanied by a variable number of dysmorphic features. It is usually sporadic although a few familial cases have been described. In a prospective study of 33 patients with sporadic SRS, we have studied the parent of origin of chromosome 7 using variable number tandem repeat (VNTR) or microsatellite repeat markers and have identified two patients with maternal uniparental disomy of chromosome 7 (mUPD7). In one family, inconsistent inheritance of paternal alleles of markers on chromosomes other than 7 led to their exclusion from further study. The probands were clinically mild and symmetrical, but showed no gross clinical differences from the 30 patients with chromosome 7 derived from both parents.     

Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions

The main features of Silver-Russell syndrome (SRS) are pre- and postnatal growth restriction and a characteristic small, triangular face. SRS is also accompanied by other dysmorphic features including fifth finger clinodactyly and skeletal asymmetry. The disorder is clinically and genetically heterogeneous, and various modes of inheritance and abnormalities involving chromosomes 7, 8, 15, 17, and 18 have been associated with SRS and SRS-like cases. However, only chromosomes 7 and 17 have been consistently implicated in patients with a strict clinical diagnosis of SRS. Two cases of balanced translocations with breakpoints in 17q23.3-q25 and two cases with a hemizygous deletion of the chorionic somatomammatropin gene (CSH1) on 17q24.1 have been associated with SRS, strongly implicating this region. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in up to 10% of SRS patients, with disruption of genomic imprinting underlying the disease status in these cases. Recently, two SRS patients with a maternal duplication of 7p11.2-p13, and a single proband with segmental mUPD for the region 7q31-qter, were described. These key patients define two separate candidate regions for SRS on both the p and q arms of chromosome 7. Both the 7p11.2-p13 and 7q31-qter regions are subject to genomic imprinting and the homologous regions in the mouse are associated with imprinted growth phenotypes. This review provides an overview of the genetics of SRS, and focuses on the newly defined candidate regions on chromosome 7. The analyses of imprinted candidate genes within 7p11.2-p13 and 7q31-qter, and gene candidates on distal 17q, are discussed.


Keywords: Silver-Russell syndrome; imprinting; mUPD(7); candidates     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver‐Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver‐Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well‐recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved. © 2002 Wiley‐Liss, Inc.     

No evidence of uniparental disomy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retardation

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long-term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver-Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n = 13) or SRS (n = 10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR.     

The genetic aetiology of Silver-Russell syndrome

Silver-Russell syndrome (SRS MIM180860) is a disorder characterised by intrauterine and/or postnatal growth restriction and typical facies. However, the clinical picture is extremely diverse due to numerous diagnostic features reflecting a heterogeneous genetic disorder. The mode of inheritance is variable with sporadic cases also being described. Maternal uniparental disomy (mUPD) of chromosome 7 accounts for 10% of SRS cases and many candidate imprinted genes on 7 have been investigated. Chromosome 11 has moved to the forefront as the key chromosome in the aetiology, with reports of methylation defects in the H19 imprinted domain associated with the phenotype in 35-65% of SRS patients. Methylation aberrations have been described in a number of other imprinted growth related disorders such as Beckwith-Wiedmann syndrome. This review discusses these recent developments as well as the previous work on chromosome 7. Other candidate genes/chromosomal regions previously investigated are tabled.     

Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation

Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver-Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype. Detailed clinical analysis confirmed the molecular finding in the patient indicating that the 14q32 epimutation was clinically preponderant. The parallel occurrence of upd(7q)mat and a DLK1/GTL2 hypomethylation in the same patient is a unique finding. Indeed, both disturbances might have occurred coincidentally, but it can also be hypothesized that the upd(7q)mat as the initial genomic mutation represents a trans-acting mutation causing an aberrant methylation in 14q32.     

Severe Silver-Russell syndrome and translocation (17;20) (q25;q13)

An 8-year-8-month-old girl with Silver-Russell syndrome (SRS) and a paternally inherited balanced t(17;20)(q25;q13) is described. This observation suggests that an SRS gene(s) maps on chromosome 17 or 20 and that the patient phenotype resulted from either unmasking of heterozygosity or genomic imprinting via paternal disomy.     

Mosaic maternal uniparental disomy of chromosome 11 in a patient with Silver-Russell syndrome

Silver-Russell syndrome (SRS) is a clinically heterogeneous disorder characterised mainly by intrauterine and postnatal growth retardation. While maternal uniparental disomy of chromosome 7 is found in 5-10% of SRS patients, recently genetic and epigenetic mutations affecting the imprinting centres on chromosome 11p15 have been reported in up to 64% of patients. Chromosome 11p15 abnormalities reported in SRS include methylation defects in the imprinting centre 1 (ICR1) and maternally inherited duplications involving all or part of the imprinted region of 11p15. Here we report the first published case of SRS with mosaic maternal uniparental disomy of chromosome 11.     

Review and meta-analysis of systematic searches for uniparental disomy (UPD) other than UPD 15

All systematic searches for uniparental disomy (UPD) so far published and comprising clinically defined populations (Silver-Russell syndrome/primordial growth retardation (SRS/PGR) (n = 14), multiple malformations (n = 2), or rare syndromes (n = 12)) or situations at risk (confined placental mosaicism (CPM) (n = 13), spontaneous abortions (n = 6), additional marker chromosomes (n = 15), balanced non-Robertsonian translocations (n = 3), or balanced Robertsonian translocations (n = 15)) were reviewed. In many studies clinical and/or cytogenetic information on fluorescent in situ hybridization (FISH) results was very scarce. Meta-analysis concerning an adequate number of cases was possible for SRS/PGR, CPM, additional marker chromosomes, and balanced Robertsonian translocations only. As expected, the highest risk for UPD was found in cases with translocations between homologous acrocentric chromosomes (11 cases with UPD of 15 investigated) and in CPM due to a meiotic error (25 of 51 cases).In prenatal investigations or in cases with a normal phenotype, translocations between nonhomologous acrocentric chromosomes implied a risk for UPD of less than 0.5%. The risks for maternal UPD 7 in cases with SRS/PGR, for UPD 15 in cases with an additional inv dup(15) marker chromosome, and for UPD of any chromosome in cases with multiple malformation/mental retardation were approximately 5.5%, and approximately 1.3%, respectively. Searches for UPD in well-defined syndromes (Brachmann-De Lange syndrome, Sotos syndrome, Rett syndrome, Weaver syndrome, or XX true hermaphroditism) were disappointing. Not a single case was found.     

Third case of paternal isodisomy for chromosome 7 with cystic fibrosis: a new patient presenting with normal growth

Many patients with maternal uniparental disomy of chromosome 7 (UPD7) have been described, mainly with intrauterine and postnatal growth retardation or with Silver-Russell syndrome. In contrast, only three cases of paternal UPD7 have been reported, all associated with recessive disorders. Here, we report on the clinical and molecular data of the third patient with paternal UPD7 and cystic fibrosis. Pre- and postnatal growth were normal. These findings support the hypothesis that paternal isodisomy for human chromosome 7 may have no phenotypic effect on growth.     

Uniparental disomy 7 in Silver--Russell syndrome and primordial growth retardation

Maternal uniparental disomy for the entire chromosome 7 hasso far been reported in three patients with intrauterine andpostnatal growth retardation. Two were detected because theywere homozygous for a cystic fibrosis mutation for which onlythe mother was heterozygous, and one because he was homozygousfor a rare COL1A2 mutation. We investigated 35 patients witheither the Silver-Russell syndrome or primordial growth retardationand their parents with PCR markers to search for uniparentaldisomy 7. Four of 35 patients were found to have maternal disomy,including three with isodisomy and one with heterodisomy. Thedata confirm the hypothetical localization of a maternally imprintedgene (or more than one such gene) on chromosome 7. It is suggestedto search for UPD 7 in families with an offspring with sporadicSilver-Russell syndrome or primordial growth retardation.     

An interstitial deletion of chromosome 7 at band q21: a case report and review

We report on a girl with moderate developmental delay and mild dysmorphic features. Cytogenetic investigations revealed a de novo interstitial deletion at the proximal dark band on the long arm of chromosome 7 (7q21.1-q21.3) in all analyzed G-banded metaphases of lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) and molecular studies defined the breakpoints at 7q21.11 and 7q21.3 on the paternal chromosome 7, with the proximal deletion breakpoint between the elastin gene (localized at 7q11.23) and D7S2517, and the distal breakpoint between D7S652 and the COL1A2 gene (localized at 7q21.3-q22.1). Deletions of interstitial segments at the proximal long arm of chromosome 7 at q21 are relatively rare. The karyotype-phenotype correlation of these patients is reviewed and discussed. The clinical findings of patients with a deletion at 7q21 significantly overlap with those of patients with maternal uniparental disomy of chromosome 7 (matUPD(7)) and Silver-Russell syndrome (SRS, OMIM 180860). Therefore, 7q21 might be considered a candidate chromosomal region for matUPD(7) and SRS.     

Silver-Russell 综合征研究进展

Silver-Russell综合征是一组遗传异质性的疾病,主要临床表现为胎儿严重的宫内生长发育迟缓及出生后生长发育迟缓和矮身材。1953年Silver等首先报道报告了2例先天性的躯体不对称、低体重、矮身材、尿中促性腺激素增高的病例。以后陆续有零散病例报告。目前研究发现此病有三种遗传方式:即母源第7号染色体单亲双体、常染色体显性遗传及常染色体隐性遗传。本文综述了Silver-Russell综合征的临床诊断标准及研究进展。     

Paternally inherited deletion of CSH1 in a patient with Silver-Russell syndrome.

In a continuing study on the aetiology of Silver-Russell syndrome (SRS), we detected a patient with a heterozygous deletion in the growth hormone gene cluster (17q22-q24). The deletion of the chorionic somatomammotrophin hormone 1 (CSH1) gene was inherited from the patient's father. The patient shows typical symptoms of SRS. Though deletions of CSH1 have been reported without any phenotypic consequences, the heterozygous deletion might be involved in the aetiology of SRS in the case presented here. Apart from other observations in SRS, like maternal uniparental disomy 7, changes in the genomic region 17q22-qter might be responsible for the expression of this syndrome for at least some of the patients, leading to the heterogeneity of SRS.     

Two sisters with Silver-Russell phenotype

Silver-Russell syndrome (SRS) is a well recognizable syndrome, but the etiology of SRS seems to be heterogeneous. SRS is listed in Mendelian Inheritance in Man as an autosomal dominant disorder because most described cases have been of sporadic occurrence, and most likely were caused by de novo autosomal dominant mutation, and because families with apparent dominant transmission of a SRS phenotype have been described. Still, in a few families, autosomal recessive inheritance has been suggested. We describe two sisters who meet the criteria for SRS proposed by Price et al. [1999]. The parents had normal facial features, normal height, and normal post-natal growth. This is the second well-documented case of familial recurrence of SRS that resembles an autosomal recessive inheritance pattern. Since sib recurrence is so rare in SRS, other modes of inheritance should be considered. The finding of maternal uniparental disomy 7 (mUPD7) in 10% of SRS cases suggests that lack of paternally expressed imprinted gene(s) or overexpression of maternal imprinted gene(s) on chromosome 7 cause SRS. The recurrence in sibs could be caused by a mutation in the imprinted gene or imprinting center carried by one parent. Alternatively, recurrence in sibs could represent germ line mosaicism for a dominant mutation in one of the parents.     

Human PEG1/MEST, an imprinted gene on chromosome 7

The mouse Peg1/Mest gene is an imprinted gene that is expressed particularly in mesodermal tissues in early embryonic stages. It was the most abundant imprinted gene among eight paternally expressed genes (Peg 1-8) isolated by a subtraction-hybridization method from a mouse embryonal cDNA library. It has been mapped to proximal mouse chromosome 6, maternal duplication of which causes early embryonic lethality. The human chromosomal region that shares syntenic homology with this is 7q21-qter, and human maternal uniparental disomy 7 (UPD 7) causes apparent growth deficiency and slight morphological abnormalities. Therefore, at least one paternally expressed imprinted gene seems to be present in this region. In this report, we demonstrate that human PEG1/MEST is an imprinted gene expressed from a paternal allele and located on chromosome 7q31-34, near D7S649. It is the first imprinted gene mapped to human chromosome 7 and a candidate for a gene responsible for primordial growth retardation including Silver-Russell syndrome (SRS).      

Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients

The association of uniparental disomy (UPD) and short stature has been reported for different chromosomes and in several conditions. Therefore, we investigated a cohort of 21 patients referred because of intrauterine and postnatal growth retardation for UPD of chromosomes 2, 7, 9, 14, 16, and 20. Typing of short tandem repeats showed maternal UPD(14) and maternal UPD(20) in two cases. In the first case, an interstitial UPD(14) was detected and the growth retarded newborn showed some additional clinical signs in common with the putative "maternal UPD(14) syndrome". The maternal UPD(20) patient showed minor features. However, since it is only the second maternal UPD(20) case it is too early to delineate a specific syndrome and the role of this constitution in growth remains to be investigated. Our data suggest that searching for UPD in growth retarded patients is a helpful approach to getting more information on the role of UPD in growth retardation. Based on our results, general considerations and indications for UPD testing are discussed.


Keywords: uniparental disomy 14; uniparental disomy 20; growth retardation; Silver-Russell syndrome