Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology

The limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of diseases characterized by shoulder-girdle and pelvic muscle weakness and wasting. LGMD 2E is an autosomal recessively inherited form of the disease caused by mutations in the β-sarcoglycan (SGCB) gene located at 4q12. In this report, we describe a patient who demonstrates non-Mendelian inheritance of a homozygous missense mutation in SGCB resulting in disease expression. A combination of single-nucleotide polymorphism (SNP) array technology and microsatellite analysis revealed the occurrence of maternal uniparental disomy (UPD) for chromosome 4 in the patient. As a consequence of segmental isodisomy at 4q12, the patient inherited two identical SGCB alleles carrying a missense mutation predicted to result in abnormal protein function. SNP array technology proved to be an elegant means to determine the most probable mechanism of UPD formation in this case, and enabled us to determine the location of recombination events along chromosome 4. In our patient, UPD likely arose from a trisomy rescue event due to maternal meiotic non-disjunction that we speculate may have been caused by abnormal recombination at the pericentromeric region. Maternal UPD 4 is a rare finding, and to our knowledge this is the first reported case of UPD in association with LGMD.     

Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy

Donnai-Barrow syndrome [Faciooculoacousticorenal (FOAR) syndrome; DBS/FOAR] is a rare autosomal recessive disorder resulting from mutations in the LRP2 gene located on chromosome 2q31.1. We report a unique DBS/FOAR patient homozygous for a 4-bp LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. The propositus inherited the mutation from his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. This is the first case of DBS/FOAR resulting from uniparental disomy (UPD) and the fourth published case of any paternal UPD 2 ascertained through unmasking of an autosomal recessive disorder. The absence of clinical symptoms above and beyond the classical phenotype in this and the other disorders suggests that paternal chromosome 2 is unlikely to contain imprinted genes notably affecting either growth or development. This report highlights the importance of parental genotyping in order to give accurate genetic counseling for autosomal recessive disorders.     

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.     

Zellweger syndrome resulting from maternal isodisomy of chromosome 1

Zellweger syndrome (ZS) is an autosomal recessive peroxisomal disorder that results from mutations in one of the peroxisome biogenesis (PEX) genes. This is the first patient reported with uniparental disomy (UPD) resulting in ZS, in this case maternal isodisomy of chromosome 1 involving reduction to homoallelism of a frameshift mutation within PEX 10. Other reported cases of UPD1, and evidence for the imprinting of genes on chromosome 1, are reviewed. The molecular findings in this patient have important implications for molecular testing and genetic counseling in ZS.     

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.     

Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137-143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heterodisomy, 59 X isodisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterdisomy, 53 X isodisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.     

Third Prader‐Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader‐Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype–genotype differences are useful to guide the work‐up of patients with suspected PWS and to provide prognostic counseling for families. Am. J. Med. Genet. 93:215–218, 2000. © 2000 Wiley‐Liss, Inc.     

The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.     

Difficulties of genetic counseling and prenatal diagnosis in a consanguineous couple segregating for the same translocation (14;15) (q11;q13) and at risk for Prader-Willi and Angelman syndromes

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with a loss of function of imprinted genes in the 15q11-q13 region mostly due to deletions or uniparental disomies (UPD). These anomalies usually occur de novo with a very low recurrence risk. However, in rare cases, familial translocations are observed, giving rise to a high recurrence risk. We report on the difficulties of genetic counseling and prenatal diagnosis in a family segregating for a translocation (14;15)(q11;q13) where two consanguineous parents carry the same familial translocation in this chromosome 15 imprinting region. Both children of the couple inherited a chromosomal anomaly leading to PWS. However, a paternal 15q11-q13 deletion was responsible for PWS in the first child, whereas prenatal diagnosis demonstrated that PWS was associated with a maternal 15q11-q13 UPD in the fetus. This report demonstrates that both conventional and molecular cytogenetic parental analyses have to be performed when a deletion is responsible for PWS or AS in order not to overlook a familial translocation and to insure reliable diagnosis and genetic counseling.     

Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1

We report on the first case of fumarase deficiency (FD) caused by uniparental isodisomy. An affected patient was found to be homozygous for the P131R mutation in the FH gene. In this nonconsanguineous family, the unaffected father was found to be heterozygous for the same mutation, and the mother was found to be homozygous wild-type. Analysis of chromosome 1 markers showed that the patient inherited both paternal alleles with complete absence of the maternal homolog. The two copies of the paternal chromosome 1 are heterodisomic for most of the chromosome except the distal 1q region which is isodisomic for the mutant alleles of the FH gene. The genotypes of other chromosome markers are consistent with the patient inheriting alleles from both parents. Although FD is an autosomal recessive disorder, the effects of uniparental disomy (UPD) should be considered in genetic counseling since the recurrence risk of an affected child is significantly reduced when the disorder is due to UPD.     

Maternal uniparental heterodisomy of chromosome 17 in a patient with nephropathic cystinosis

We report maternal uniparental disomy of chromosome 17 (mat UPD17) in a 2.5-year-old girl presenting infantile cystinosis. This patient was homozygous for the 57 kb deletion encompassing the CTNS gene, frequently found in patients from the European origin. The proband''s mother was heterozygous for the deletion and the father did not carry the deletion. We carried out haplotype analysis with polymorphic markers spanning the whole chromosome 17. Informative markers showed the presence of two maternal alleles but no paternal allele for regions spanning the 17q arm and the proximal half of 17p, and only one maternal allele on the distal 17p arm. As deletion of half of 17p is probably not viable, these results suggest mat UPD17 with heterodisomy of 17q and proximal 17p and isodisomy of distal 17p. This is the first demonstration of mat UPD17, in particular of isodisomy 17p, in cystinosis.     

Fatal Malonyl CoA Decarboxylase Deficiency Due to Maternal Uniparental Isodisomy of the Telomeric End of Chromosome 16

Malonic aciduria is a rare autosomal recessive disorder caused by deficiency of malonyl-CoA decarboxylase, encoded by the MLYCD gene.
We report on a patient with clinical presentation in the neonatal period. Metabolic investigations led to a diagnosis of malonyl-CoA decarboxylase deficiency, confirmed by decreased activity in cultured fibroblasts. High doses of carnitine and a diet low in lipids led to a reduction in malonic acid excretion, and to an improvement in his clinical conditions, but at the age of 4 months he died suddenly and unexpectedly. No autopsy was performed.
Molecular analysis of the MLYCD gene performed on the proband's RNA and genomic DNA identified a previously undescribed mutation (c.772–775delACTG) which was homozygous. This mutation was present in his mother but not in his father; paternity was confirmed by microsatellite analysis. A hypothesis of maternal uniparental disomy (UPD) was investigated using fourteen microsatellite markers on chromosome 16, and the results confirmed maternal UPD. Maternal isodisomy of the 16q24 region led to homozygosity for the MLYCD mutant allele, causing the patient's disease. These findings are relevant for genetic counselling of couples with a previously affected child, since the recurrence risk in future pregnancies is dramatically reduced by the finding of UPD. In addition, since the patient had none of the clinical manifestations previously associated with maternal UPD 16, this case provides no support for the existence of maternally imprinted genes on chromosome 16 with a major effect on phenotype.     

Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (<6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease.     

First patient with trisomy 21 accompanied by an additional der(4)(:p11 --> q11:) plus partial uniparental disomy 4p15-16

We report on a rare additional numerical chromosomal aberration in a child with Down syndrome due to free trisomy 21. The karyotype showed 48,XY,+21,+mar after GTG banding, with the marker present in 80% of cells. The supernumerary marker chromosome (SMC) was as small as approximately one-third of 18p, and with the recently developed centromere-specific multi-color fluorescence in situ hybridization (cenM-FISH) technique, it was shown that the SMC was a derivative chromosome 4. The SMC was not specifically stained by arm-specific probes for chromosome 4; thus, it has been described as der(4)(:p11 --> q11:). Microsatellite analysis resulted in a partial maternal uniparental isodisomy (UPD) for chromosome 4p15-16 and a maternal origin for two chromosomes 21. Until now only two similar cases have been described in the literature, but without clarifying the origin of the SMC and without looking for an additional UPD. This is the only reported case of a UPD 4p in a liveborn child.     

Congenital ichthyosis in Prader–Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD

Prader–Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11‐q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader–Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15‐related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co‐occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15‐related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.     

Uniparental disomy of multiple chromosomes in two cases with a complex phenotype

Uniparental disomy (UPD) is the inheritance of both chromosomal homologs from one parent. Depending on the chromosome involved and the parental origin, UPD may result in phenotypic abnormalities due to aberrant methylation patterns or unmasking recessive conditions in isodisomic regions. UPD primarily originates from somatic rescue of a single meiotically-derived aneuploidy, most commonly a trisomy. Double UPD is exceedingly rare and triple UPD has not been previously described. Here, we report two unrelated clinical cases with UPD of multiple chromosomes; an 8-month-old male with maternal isodisomy of chromosome 7 and paternal isodisomy of chromosome 9, and a 4-week-old female with mixed paternal UPD for chromosomes 4, 10, and 14. These cases also demonstrate that although extremely rare, the detection of AOH on two or more chromosomes may warrant additional clinical and laboratory investigation such as methylation and STR marker analysis, especially when involving chromosomes known to be associated with imprinting disorders.     

The 11 kb FGA deletion responsible for congenital afibrinogenaemia is mediated by a short direct repeat in the fibrinogen gene cluster

Congenital afibrinogenaemia is an autosomal recessive disorder characterised by the complete absence of detectable fibrinogen. We previously identified the first known causative mutations for this disorder in a non-consanguineous Swiss family. The four affected male individuals (two brothers and their first two cousins) were shown to have homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data suggested that the deletions occurred on three distinct ancestral chromosomes, implying that the FGA region of the fibrinogen locus is susceptible to deletion by a common mechanism, but the sequences responsible for the recombination remained to be identified. Here, we report the detailed characterisation of the deletion by nucleotide sequence analysis of all three deletion junctions and comparison with normal sequences. We found that all three deletions were identical to the base-pair and probably resulted from non-homologous (illegitimate) recombination. The centromeric and telomeric deletion junctions featured both a 7 bp direct repeat, AACTTTT, situated in FGA intron 1 and in the FGA-FGB intergenic sequence and a number of inverted repeats which could be involved in the generation of secondary structures. Analysis with closely linked flanking polymorphic markers revealed the existence of at least two haplotypes, further suggesting independent origins of the deletions in this family.     

一个纤维蛋白原γ链Arg275His突变导致的遗传性异常纤维蛋白原血症家系

目的　对一个遗传性异常纤维蛋白原血症家系进行表型和基因型分析。方法　采集家系3代5人外周血,吸取上层血浆用血凝仪检测活化部分凝血酶原时间、凝血酶原时间、凝血酶时间、蛋白C活性、蛋白S活性和抗凝血酶活性,纤维蛋白原活性和抗原分别用Clauss法和免疫比浊法进行检测。以常规酚-氯仿法抽提家系所有成员外周血基因组DNA,PCR扩增纤维蛋白原基因FGA、FGB和FGG所有外显子及其侧翼序列,PCR产物纯化后直接测序以检测基因突变。结果　先证者活化部分凝血酶原时间、凝血酶原时间正常,凝血酶时间超出正常上限值2倍以上,纤维蛋白原活性明显下降,抗原也低于正常范围,且活性显著低于抗原;其母表型检测结果与之相似。基因分析显示先证者呈纤维蛋白原FGG基因第8外显子g.5 6 78G>A杂合碱基置换,导致Arg2 75 His错义突变,该突变来源于母系。结论　纤维蛋白原γ链Arg2 75 His杂合错义突变是引起该家系异常纤维蛋白原血症的原因。     

Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15

Prader-Willi syndrome (PWS) is a complex multiple anomaly syndrome that has been shown to result from deficient expression of paternal chromosome 15(q11-q13). In most cases, it is caused either by deletion of this region in the paternally inherited chromosome 15 or by maternal uniparental disomy (UPD) of chromosome 15. In order to determine whether there are phenotypic differences between patients whose PWS is caused by these two different mechanisms, 54 affected individuals (37 with deletion, 17 with UPD) were personally examined and studied using molecular techniques. The previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the two groups, those with UPD were less likely to have a “typical” facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average. Possible mechanisms by which these differences could occur and the implications of these differences for diagnosis are described. Am. J. Med. Genet. 68:433–440, 1997. © 1997 Wiley-Liss, Inc.     

Complete maternal isodisomy of chromosome 8 in an individual with an early-onset ileal carcinoid tumor

Uniparental disomy (UPD) is a condition in which diploid individuals possess a chromosome pair from a single parent. In some instances, UPD causes an abnormal phenotype due to imprinting effects, reduction to homozygosity at recessive disease loci, or trisomy mosaicism. Here we report the first account of an individual with apparently nonmosaic complete maternal isodisomy of chromosome 8. This individual was identified during routine genotyping in a genomewide search for type 2 diabetes susceptibility genes, although he does not have diabetes. He is of normal appearance, stature, and intelligence, but there is an unusual history of early onset ileal carcinoid. The discovery of other maternal UPD 8 cases will be necessary to define whether this condition causes a distinct phenotype.