A novel microdeletion at chromosome 2q31.1-31.2 in a three-generation family presenting duplication of great toes with clinodactyly

HOXD gene cluster maps to chromosome 2q31 and plays a key role in embryonic limb morphogenesis. Mutations of the HOXD13 and HOXD10 genes have been found to be associated with digital and limb malformations. In addition, dysregulation of HOXD gene cluster has been proposed to account for the limb abnormalities in patients with chromosome 2q rearrangements. In this report, we investigated a three-generation family presenting clinical phenotypes of duplication of great toes, tapering fingers, and clinodactyly of the fifth finger in both hands, which were transmitted in a dominant fashion in this family. We identified and validated an interstitial microdeletion of ∼3.4 Mb at chromosome 2q31.1-31.2 by array-based comparative genomic hybridization, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction that cosegregates with the clinical phenotypes in this family. The microdeletion removes 30 labeled genes including the entire HOXD gene cluster, suggesting that the digital abnormalities of this family may be attributed to the haploinsufficiency of the HOXD gene cluster. The delineation of the microdeletion region may contribute to the genotype–phenotype correlation study in patients with genomic rearrangements of the long arm of chromosome 2 and helps to understand the pathogenesis of haploinsufficiency of the HOXD gene cluster.     

Duplication in chromosome 15q in a boy with the Prader-Willi syndrome; further cytogenetic confusion

We describe a six-year-old boy with the typical features of Prader-Willi syndrome. Cytogenetic investigation revealed a chromosome aberration that has not been described yet, i.e. a duplication in the proximal half of 15q. Based upon banding-pattern the exact nature of the duplicated part could not be delineated. Both parents had a normal karyotype. Various hypotheses concerning the relationship between Prader-Willi syndrome and various chromosome 15 abnormalities are discussed.     

Duplication of 9q12-q33: A case report and implications for the dup(9q) syndrome

We report on a case of inborn errors of metabolism in association with extensive Mongolian spots. We suggest that this association may be due to a disequilibrium of metabolism during embryonic development. © 1993 Wiley-Liss, Inc.     

Two cases with interstitial deletions of chromosome 2 and sex reversal in one

We present two children with de novo interstitial deletions of the long arm of chromosome 2 (karyotypes 46,XY, del(2)(q31.1q31.3) and 46,XY, del(2)(q24.3q31.3), respectively). The first child had severe learning difficulties, growth retardation, unilateral ptosis, small palpebral fissures, a cleft uvula, and bilateral cutaneous syndactyly of the second and third toes. Despite her male karyotype, she had female external genitalia with hypoplasia of the clitoris and labia minora. This is the first reported case of feminization of the external genitalia in a genotypic male with an interstitial deletion of chromosome 2q31 and adds to the growing amount of evidence for a gene involved in sex determination in this chromosome region. The second child had severe mental and growth retardation, ptosis, down-slanting palpebral fissures, low-set ears, micrognathia, finger camptodactyly, and brachysyndactyly of the second to fifth toes. The clinical manifestations associated with deletions of 2q31 to 2q33 are similar to those found with proximal deletions at 2q24 to 2q31 and of band 2q24, suggesting that the phenotype may result from haploinsufficiency for one or more genes located at 2q31. Microsatellite marker studies showed that both children had paternally derived deletions that included the HOXD gene cluster and the EVX2, DLX1, and DLX2 genes known to be important in limb development. Am. J. Med. Genet. 86:75–81, 1999. © 1999 Wiley-Liss, Inc.     

Duplication 14(q24.3q31) in a father and daughter: Delineation of a possible imprinted region

A number of clinical reports have described children with a variety of congenital anomalies in association with uniparental disomy (upd) of chromosome 14, suggesting that at least some genes on chromosome 14 are subject to parent of origin, or imprinting, effects. However, little else is known about this putative imprinting of chromosome 14. Both maternal and paternal upd have been observed, but a consistent phenotype has only been suggested for the former. Here we report on a child with developmental delay, microcephaly, distinct facial findings, and who has a duplication of 14q24.3q31. The same cytogenetic abnormality was found in her phenotypically normal father. We hypothesize that this segment of chromosome 14 contains maternally silenced genes, and that this duplicated segment defines an imprinted region on chromosome 14. Alternatively, this cytogenetic duplication may be unrelated to the girl's phenotypic anomalies, and this duplication may contain genes that are not subject to dosage effect. Am. J. Med. Genet. 71:361–365, 1997. © 1997 Wiley-Liss, Inc.     

Duplication of (2)(q11.1‐q13.2) in a boy with mental retardation and cleft lip and palate: Another clefting gene locus on proximal 2q?

A 4‐year‐old boy with left cleft lip and cleft palate, multiple minor anomalies and developmental delay revealed an abnormal chromosome 2 with enlarged proximal long arm, de novo, in his karyotype. Fluorescence in situ hybridization with a chromosome 2 library and band‐specific YACs confined the duplicated segment to 2q11.1‐q13.2 and indicated a direct tandem duplication due to unbalanced crossover between chromatids. © 2002 Wiley‐Liss, Inc.     

Duplication of part of chromosome 1q: Clinical report and review of literature

We report a male infant with a 47,XY,+der(22),t(1;22)(q32;q11)pat karyotype. Thus, he has duplication of chromosomes 1(q32→qter) and 22(pter→q11). Six patients with dup 1(q32→qter) and eight with dup 1(q42→qter) have been described. These two groups of patients share several manifestations, including postnatal growth retardation; relative macrocephaly with widely separated sutures or large fontanelles; prominent forehead; highly arched palate; micrognathia; downward slant of the palpebral fissures; broad, flat nasal bridge; and apparently low-set, malformed ears. Although many of these abnormalities are nonspecific, partial duplication of 1q should be considered in infants with relative macrocephaly, large fontanelles, and downward slant of the palpebral fissures. Our patient had duplication of the part of chromosome 22 that may be associated with the clinically variable cat-eye syndrome. Patients with dup 22(pter→q11) may also have downward slant of the palpebral fissures, micrognathia, and apparently low-set, malformed ears. The structural gene locus for β-glucosidase has been mapped to chromosome 1. β-Glucosidase activity in fibroblasts from our patient was normal, and his parents' activities were not significantly different from those of control individuals. Therefore, either the locus for this enzyme is not present on 1(q32→qter) or the enzyme does not consistently show a substantial gene-dose effect.     

Duplication 3q: Severe manifestations in an infant with duplication of a short segment of 3q

A patient with duplication of a short segment of 3q (3q21→26) without apparent deletion of 3 or of other chromosomes provided a further opportunity to study manifestations of this abnormality. The proposita had a broad nasal bridge, anteverted nostrils, webbed neck, and clinodactyly V in addition to congenital heart disease, limb abnormalities, cleft palate, and severe developmental delay. The infant did not have the hirsutism and synophrys present in other cases.     

Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families

Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3-p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3-p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.     

Duplication of chromosome region 4q28.3‐qter in monozygotic twins with discordant phenotypes

We describe monozygotic twins with partially discordant phenotypes who were found to have a duplication of chromosome region 4q28.3‐qter. The duplicated region of chromosome 4 resulted from an unbalanced segregation of a balanced maternal (4;22)(q28.3;p13) translocation. Duplication of the long arm of chromosome 4 has been described in >60 patients; however, it usually results from the unbalanced segregation of a parental balanced translocation and has an associated monosomy. Twenty cases of dup 4q without an associated monosomy have been reported, and this is the only case of dup 4q28.3‐qter. All cases of dup 4q are reviewed, and phenotypic aspects are analyzed. Issues of monozygotic twinning and other birth defects also are addressed. Am. J. Med. Genet. 94:125–140, 2000. © 2000 Wiley‐Liss, Inc.     

Prenatal diagnosis of a constitutional interstitial deletion of chromosome 5 (q15q31.1) presenting with features of congenital contractural arachnodactyly

Prenatal diagnosis of a constitutional interstitial deletion of chromosome 5 (q15q31.1) in a 30-year-old woman is reported. At 21 weeks of pregnancy, routine fetal ultrasounds showed the presence of apparently isolated bilateral club feet. Fetal karyotyping documented an interstitial deletion of the long arm of chromosome 5: 46,XX,del(5) (q15q31) in all 50 analyzed metaphases. Because such deletion is associated with severe psychomotor retardation, the pregnancy was terminated. Postmortem karyotyping of skin fibroblasts confirmed the presence of this interstitial de novo deletion in all mitoses. The breakpoints on 5q were analyzed by fluorescent in situ hybridization and were localized at 5q15 and q31.1. This case illustrates the importance of fetal karyotyping in cases of isolated club feet. At autopsy, the fetus presented had minor anomalies and contractures of knee and hip joints. These clinical findings could fit the diagnosis of congenital contractural arachnodactyly (CCA) or Beals syndrome. CCA is caused by a defect in the fibrillin-2 (FBN2) gene. This gene was previously mapped on 5q23-31. Our molecular studies of both parents and the fetus, using an intragenic polymorphic GT repeat, showed that the FBN2 gene was deleted in the fetus and that the de novo interstitial deletion occurred on the paternally inherited chromosome 5. Thus, CCA may be caused by a loss of function of the FBN2 gene. Clinical findings in this fetus and those of other described cases with interstitial 5q deletions are reviewed, and similarities with CCA are stressed. Am. J. Med. Genet. 77:188–197, 1998. © 1998 Wiley-Liss, Inc.     

Genetic effects of a 13q31.1 microdeletion detected by noninvasive prenatal testing (NIPT)

Microdeletions of chromosome 13q31.1 are relatively rare. These types of deletions may cause different genetic effects on genotypes and/or phenotypes. There are several ways to detect microdeletions; noninvasive prenatal testing (NIPT) is the newest detection method. In this study, we aimed to investigate the genetic effects of a 13q31.1 microdeletion detected by NIPT and to reconfirm the feasibility of this procedure in predicting sub-chromosomal copy number variations (CNVs). The 13q31.1 microdeletion, which has previously been described as a disease-associated fragment, was detected by NIPT in a pregnant woman. To validate the finding and to explain the origin of this sub-chromosomal CNV, we collected fetal amniotic fluid and parental blood samples and tested the samples using array-based comparative genomic hybridization (aCGH). Karyotype analysis was performed on all of the samples to rule out balanced or mosaic anomalies. The aCGH results confirmed the NIPT findings. We detected the same type of microdeletion in the fetus and the mother via aCGH. The mother had a normal phenotype; therefore, in a post-test genetic counseling session, we predicted a normal phenotype for the fetus. After delivery, the normal phenotype of the newborn confirmed our prediction. Based on the present study, this 13q31.1 microdeletion may be considered as a chromosomal polymorphism. This study also reconfirmed the feasibility of obtaining a molecular karyotype of a fetus via NIPT.     

Duplication 16q12.1-q22.1 characterized by array CGH in a girl with spina bifida

We report a 7-year-old girl with spina bifida carrying a complex chromosome abnormality resulting in duplication 16q12.1-q22.1. An abnormal karyotype was identified involving the long arm of chromosome 11 and fluorescent in situ hybridization (FISH) to metaphase chromosomes revealed an insertion of part of chromosome 16 on chromosome 11. A detailed mapping of the chromosome abnormality using whole genome array based comparative genomic hybridization (CGH) of the patient DNA revealed a duplication 16q12.1-q22.1 corresponding to gain of 19.8Mb of DNA without any detectable loss of genetic material on chromosome 11. The karyotype is defined as 46,XX,der(11)ins(11;16)(q13;q12.1q22.1). We present here the clinical findings and a fine mapping of the associated structural chromosome abnormalities. We suggest that a gene dosage imbalance of 16q12.1-q22.1 is associated with spina bifida in the patient.