De novo proximal interstitial deletions of 14q: Cytogenetic and molecular investigations

We report on 2 unrelated patients who had chromosome analysis performed because of psychomotor delay, Failure to thrive, and minor anomalies. Each patient had a novel proximal 14q deletion (q11.2 to q21.1 in patient 737 and q12 to q22 in patient 777). Polymorphic (C-A)_n microsatellite markers distributed along the length of chromosome 14q were examined in both patients and their parents in order to determine which marker loci were deleted. The deletion in patient 737 was found to be paternal in origin, based on the analysis of 2 marker loci (D14S54 and D14S70), thus assigning these loci to the deleted interval q11.2 q21.1. Furthermore, 3 loci were not deleted (TCRD, D14S50, and D14S80), suggesting that they are within or proximal to 14q11.2. In the other family (patient 777), none of the markers were fully informative, but the deleted chromosome was determined to be paternally derived based on cytogenetic heteromorphisms. Despite having overlapping proximal 14q deletions, these 2 patients shared few phenotypic similarities except for failure to thrive, micrognathia, and hypoplasia of the corpus callosum. Therefore, a distinct proximal 14q deletion syndrome is not yet apparent. However, the molecular analyses facilitated the localization of several 14q DNA markers to the deletion regions in these 2 patients, while excluding other markers from each deletion. © 1994 Wiley-Liss, Inc.     

Paracentric inversion of chromosome 14: A case report

Summary A new case of familial heterozygous paracentric inversion in the long arm of chromosome 14 [inv(14)(q22q32)] is presented. The rearrangement was first ascertained in a fetus examined due to advanced maternal age, and then detected in the father. The phenotypes of the newborn and the father were completely normal. The parents had no history of spontaneous abortion. With reference to previous reports, the risk of clinical abnormalities are discussed for bothde novo and familial paracentric inversions of chromosome 14.     

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.     

Postzygotic D/D translocation homozygosity associated with recurrent abortions

A Robertsonian translocation involving homologous D chromosomes was found in two cases with a history of recurrent abortions. In the first case the propositus was a 37-year-old phenotypically normal man who had a balanced t(14q14q) translocation. In the second case, a 27-year-old phenotypically normal woman was found to be a balanced t(15q15q) translocation carrier. The recurrent abortions in both cases were probably owing to this translocation.     

Submicroscopic deletion in 14q32.3 through a de novo tandem translocation between 14q and 21p

We describe a male child with craniofacial anomalies, postnatal onset growth retardation, microcephaly, multiple minor anomalies, hearing loss, and moderate delay of mental and statomotor development. He carries a previously undescribed tandem translocation between the long arm of chromosome 14 and the short arm of chromosome 21 that arose de novo. As proven by fluorescence in situ hybridization a microdeletion not detectable with high-resolution G-banding occured in 14q32.3, the terminal band on the long arm of chromosome 14. The resulting phenotype includes most abnormalities encountered in patients with terminal 14q32.3 deletions but in addition includes some characteristics of the ring chromosome 14 syndrome. Am. J. Med. Genet. 80:443–447, 1998. © 1998 Wiley-Liss, Inc.     

Identification of the chromosome 14 origin of a C-negative marker associated with a 14q32 deletion by chromosome painting

A constitutional chromosome 14 rearrangement was observed in a female with a psychodevelopmental disorder. Karyotype analysis using a variety of chromosome techniques, QFQ, GTG, CBG, Ag-NOR and DA-DAPI, showed a deletion of chromosome 14q32.1-qter region in association with a supernumerary marker chromosome. The marker, resembling a submetacentric, approximately half the size of a G group chromosome is C band and Ag-NOR negative. The heteromorphism of the satellites showed that the deleted chromosome 14 is paternal in origin. Chromosome painting using an Alu-PCR probe specific for the human chromosome 14 and fluorescent in situ hybridization (FISH) showed that the marker contains chromosome 14q32 sequences. It is likely that the marker was generated from the deleted chromosome 14 region through a complex rearrangement.     

Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology

Age of onset is the most robust clinical feature demarcating aetiologic subtypes of familial Alzheimer's disease. It has previously been noted that early onset disease (arbitarily below the age of 65 years) conforms to an autosomal dominant pattern of transmission. Late onset disease is generally thought to have a more complex aetiology. We present data here suggesting that early onset disease can be subdivided by genetic aetiology with which age of onset correlates. In general, those pedigrees showing linkage to the chromosome 14 locus have a mean age of onset in the forties whereas those pedigrees with an APP mutation have an age of onset in the fifties. © 1993 Wiley-Liss, Inc.     

Tetramelic mirror-image polydactyly and a de novo balanced translocation between 2p23.3 and 14q13

We report on a male infant with tetramelic mirror-image polydactyly and a de novo, balanced reciprocal translocation between 2p23.3 and 14q13. This patient suggests that a novel gene, which functions in the morphogenesis of the hands and feet along the anterior-posterior axis, may be located at 2p23.3 or 14q13. Am. J. Med Genet. 68:70–73, 1997 © 1997 Wiley-Liss, Inc.     

Partial deletion of 14q and partial duplication of 14q in sibs: Testicular mosaicism for t(14q;14q) as a common mechanism

The propositus and a subsequently born sister presented with multiple congenital anomalies. Chromosome analyses were performed initially on peripheral blood lymphocytes from the propositus and his parents: the propositus was found to have a deletion of chromosome 14 (q32.11->qter); the parents' chromosomes were normal. When the sister of the propositus was born, she was determined to have a duplication of an equivalent segment of 14qter. Chromosome studies on the parents' fibroblasts demonstrated no structural abnormality or mosaicism. The parents have an older, phenotypically normal, healthy daughter, which supports mosaicism for intragonadal t(14;14)(q32.11;q32.33) in one parent. Chromosome polymorphism comparisons show that the normal number 14 chromosome in the propositus and his sister was inherited from the mother, thus indicating paternal testicular mosaicism. Clinical findings are compared to those of other reported cases of deletion 14q and duplication 14q.     

Prenatal detection of de novo paracentric inversion 46, XX inv (14) (q22q32.1) in a normal child: Report and review of the literature

We present prenatal diagnosis and follow-up examination of an individual with a de novo paracentric inversion of the long are of chromosome 14. A literature search documented 19 other cases of paracentric inversion of 14q. The outcome of each of these cases is specified together with that of this current case. Four of the 20 cases, all XY, manifested significant abnormalities with mental retardation and microcephaly present in 3 of the 4 cases; 15% (2/13) of familial cases had abnormalities and 40% (2/5) of de novo cases had abnormalities. © 1993 Wiley-Liss, Inc.     

Maternal uniparental disomy of chromosome 14 confined to an interstitial segment (14q23-14q24.2)

Maternal uniparental disomy for the complete long arm of chromosome 14 has been reported in 14 patients to date and is associated with a specific pattern of malformation. We report a child with clinical features of this syndrome who exhibits maternal uniparental disomy confined to a specific interstitial segment of chromosome 14.     

Exclusion of linkage to 14q23-24 in a family with Holt-Oram syndrome

Holt-Oram syndrome is an autosomal dominant disorder with congenital heart defects and skeletal malformations of the upper extremities. A patient with a deletion of 14q23-24 and Holt-Oram syndrome has been described. In this report, however, genetic linkage to the 14q23-24 region is excluded in a multigeneration family with five available individuals affected with Holt-Oram syndrome. Familial Holt-Oram syndrome might be different from the syndrome with the 14q23-24 deletion.     

Unbalanced karyotype, dup 14(q13-q22), in a mother and her two children

A duplication of chromosome 14(q13-q22) caused mild mental retardation and some dysmorphic features in two children and their mother. The unbalanced karyotype did not affect the fertility of the mother. Fluorescent in situ hybridization, with a chromosome 14 specific paint, was used to confirm that the inserted material was from chromosome 14.     

Corpus callosum agenesis,multiple cysts,skin defects,and subtle ocular abnormalities with a de novo mutation [45,XX,der(5), t(5;14) (pter;q11.2)]

We report on a 2‐year‐old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single‐locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region. © 2001 Wiley‐Liss, Inc.     

Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow up

To our knowledge, 22 cases of chromosome 14 maternal uniparental disomy (UPD(14)mat) have been reported so far. The majority of cases were ascertained because of an abnormal phenotype associated with a Robertsonian translocation involving chromosome 14. We report here on a child with UPD(14)mat detected prenatally and resulting from trisomy rescue in a maternal meiosis I non-disjunction trisomic zygote. After four years of clinical follow up, in addition to intrauterine growth retardation (IUGR), only short stature and small hands and feet were observed. These clinical data as well as the ascertainment and mechanism of origin of UPD(14)mat were compared with those observed in previously reported cases. It appears that the clinical spectrum of UPD(14)mat is milder in our patient than in patients with UPD(14)mat resulting from other chromosomal mechanisms. In addition, a hypothesis based on abnormal imprinting is proposed to explain the variability of the UPD(14)mat.


Keywords: maternal UPD; chromosome 14; MCP; imprinting     

Tandem duplication of chromosome 14 (q24+q32) in male newborn with congenital malformations

A tandem duplication of 14q24→q32, estimated by G- and R-banding, was found in a male newborn with growth retardation and congenital malformations. His clinical picture is compared with that of three patients from the literature with partial trisomy for a similar segment of 14q due to a parental reciprocal translocation or a de novo translocation.     

Child with multiple congenital anomalies and mosaicism 46, XX/46,XX,del (14)(q32.3)

We report on a female infant with multiple congenital anomalies and severe developmental delay in association with a rare, terminal deletion of chromosome 14 [karyotype:mosaic. 46,XX/46,XX del (14) (q32.3) = 36%:64%]. © 1992 Wiley-Liss, Inc.     

Epimutation at human chromosome 14q32.2 in a boy with a upd(14)mat-like clinical phenotype

Recently, three reports described deletions and epimutations affecting the imprinted region at chromosome 14q32.2 in individuals with a phenotype typical for maternal uniparental disomy of chromosome 14 [upd(14)mat]. In this study, we describe another patient with upd(14)mat-like phenotype including low birth weight, neonatal feeding problems, muscular hypotonia, motor and developmental delay, small hands and feet, and truncal obesity. Conventional cytogenetic analyses, fluorescence in situ hybridization subtelomere screening, multiplex ligation-dependent probe amplification analysis of common microdeletion and microduplication syndromes, and methylation analysis of SNRPN all gave normal results. Methylation analysis at 14q32.2 revealed a gross hypomethylation of the differentially methylated regions (intergenic DMR and MEG3 -DMR). Further molecular studies excluded full or segmental upd(14)mat as well as a microdeletion within this region. Evidently, the upd(14)mat-like clinical phenotype is caused by an epimutation at 14q32.2. The clinical and molecular features of this novel case are discussed with respect to the recently published cases.     

A 2.1 Mb deletion adjacent but distal to a 14q21q23 paracentric inversion in a family with spherocytosis and severe learning difficulties

A familial q21.1q23.2-inversion on chromosome 14 that co-segregated with spherocytosis and learning difficulties or mild mental retardation was extensively investigated by bacterial artificial chromosome fluorescence in situ hybridization and array-comparative genomic hybridization. As expected, a deletion of the beta-spectrin gene SPTB, a known cause of spherocytosis, was found. More unexpectedly, this deletion was approximately 1.6 Mb distal to the 14q23.2-inversion breakpoint. The deletion spanned approximately 2.1 Mb and contained 15 annotated genes in addition to SPTB, among them PLEKHG3, a guanide nucleotide exchange factor for Rho GTPases. This gene is highly expressed in the brain and our best candidate for causing the mild mental retardation. The case illustrates that inversions can be associated with microdeletions close to but not including one of the inversion breakpoints.