Large duplication 4q25–q34 with mild clinical effect

doi:10.1016/j.anngen.2004.07.007

Annales de Génétique

Volume 47, Issue 4, October–December 2004, Pages 419-422

https://doi.org/10.1016/j.anngen.2004.07.007 Get rights and content

Abstract

We report on a 5-year-old Tunisian boy with particular dysmorphic features and mild mental retardation limited in delayed and poor language acquisition. Cytogenetic analysis using RHG banding and FISH using whole chromosome four painting probe showed a partial duplication in the long arm of chromosome four. Locus specific probes and CGH confirmed the presence of a ‘‘pure’’ partial trisomy 4q due to de novo direct tandem dup(4)(q25q34). Comparative analysis of our case with those published previously, suggests that region 4q31–q33 may be involved in the development of the 4q characteristic dysmorphic features and the distal band 4q35 may be involved in the development of microcephaly and severe mental and growth retardation.

Introduction

Isolated 4q duplication results in variable clinical features, often including growth and developmental delay, mental retardation and dysmorphic appearance [7]. ‘‘Pure’’ partial trisomy of 4q may contribute significantly to the clarification of region specific phenotypes, but very few cases were reported. Here, we report on a 5-year-old Tunisian boy with a ‘‘pure’’ partial trisomy 4q due to de novo direct tandem dup(4)(q25q34). Comparative analysis of our case with those published previously, suggests that region 4q31–q33 is critical for the development of characteristic dysmorphic features. Absence of microcephaly and severe mental and growth retardations suggests that their development is due to a trisomy of the telomeric band 4q35.

Section snippets

Clinical report

The patient, a 5-year-old boy, was the first child of healthy and unrelated Tunisian parents. Gestation was unremarkable and delivery at 39 weeks gestation was complicated by an acute foetal suffering and an emergency caesarean section was performed. Apgar scores were 5 at 1 min and 9 at 5 min. The child’s birth weight was 2500 g (3rd percentile), length was 48 cm (10th percentile) and head circumference was 34 cm (30th percentile).

The developmental milestones were within normal range with

Cytogenetic analysis

Chromosomes were obtained from lymphocytes and fibroblasts cultured from peripheral blood and cutaneous biopsy, respectively.

The Karyotype was performed using RHG banding according to usual procedures.

FISH using a chromosome four whole painting and YACs clones, 493C20 and 963K6, which maps, respectively, to 4q32.2 and 4q35.2 as probes, was performed according to usual protocols.

High molecular weight DNA was extracted from peripheral blood of the patient and used in a comparative genomic

Results

Karyotype analysis showed an enlarged long arm of one chromosome 4 in all 50 metaphase cells analyzed. FISH using chromosome four painting probe showed that the extra material was derived from chromosome 4. Chromosome anomaly consists indeed of duplication but the exact bands could not be delineated. Karyotype obtained from fibroblasts cultures showed the same chromosome four anomaly in all 20 metaphase cells analyzed. Parental chromosomes were normal.

Further study using CGH showed the presence

Discussion

For more than 60 cases of trisomy 4q previously described, most reported patients have unbalanced translocation involving chromosome four and another chromosome. [1]. Genotype-phenotype correlation was difficult because of partial chromosome monosomy associated with 4q trisomy. However, the majority of cases described with pure partial trisomy 4q results from a translocation with an acrocentric chromosome and has consequently a 4q terminal trisomy. In theses cases patients usually have

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Duplication of chromosome region 4q28.3-qter in monozygotic twins with discordant phenotypes
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A very rare case of trisomy 4q32.3-4q35.2 and trisomy 21q11.2-21q22.11 in a patient with recombinant chromosomes 4 and 21
2015, Gene
Citation Excerpt :
Two familial cases of a small region duplication of 4q31.1–q32.3 and 4q31.3–q33 also showed minimal clinical features (Goodman et al., 1997; Maltby et al., 1999). Additional duplicated material from 4q34 seems to be without major clinical effect, but telomeric band 4q35 may be involved in the development of microcephaly and severe mental and growth retardation (Elghezal et al., 2004a, 2004b). Some studies indicate that APP may be involved in DS-associated dementia, and may contribute to (but is not essential for) intellectual disability in DS (Korbel et al., 2009).
We report the case of a patient with a clinical phenotype consistent with Down Syndrome (DS) who has a novel karyotypic abnormality. Karyotypic analyses were performed to investigate the cause of two spontaneous abortions. A balanced translocation between chromosomes 4 and 21 was identified, along with an additional abnormal chromosome 21. We performed high-resolution banding, comparative genomic hybridization (CGH), and FISH studies in both the patient and her mother to define the abnormality and determine its origin. CGH revealed a gain in copy number on the long arm of chromosome 4, spanning at least 24.4 Mb, and a gain in copy number on the long arm of chromosome 21, spanning at least 16.2 Mb. FISH analysis using a chromosome 21 centromere probe and chromosome 4 long arm telomere (4pter) probe confirmed the origin of the marker chromosome. It has been confirmed by the State Key Laboratory of Medical Genetics of China that this is the first reported instance of the karyotype 47,XX,t(4;21)(q31.3;q11.2),+der(21)t(4;21)mat reported in the world.
Partial duplication of chromosome 4q (q31, q35): Auriculo-acro-renal syndrome
2008, Anales de Pediatria
La trisomía parcial 4q es una enfermedad cromosómica rara, causada por una duplicación de una porción del cromosoma 4. En la mayoría de los casos resulta de una translocación balanceada de uno de los progenitores; siendo menos frecuente la aparición de novo. Presentamos un paciente con una duplicación parcial de novo del segmento distal del brazo largo del cromosoma 4 (q31, q35) asociada a translocación robertsoniana entre los cromosomas 14 y 21; asociación previamente no descrita. En la duplicación 4q no queda bien definida la relación entre el fenotipo y las partes del segmento duplicadas, aunque parece claro que anomalías renales y/o de pulgares son una manifestación característica. Revisamos la literatura médica, y de los casos previamente descritos con trisomía q31-35 concluimos que esta región del cromosoma 4 también estaría comprometida en constituir el “síndrome de la trisomía parcial 4q” o “síndrome aurículo-acro-renal”
The partial trisomy 4q is a strange chromosomal illness. This illness is caused by the duplication of a portion of chromosome 4. In most of the cases, it is the result of a balanced translocation in one of the progenitors. The “de novo” appearance is less common. We present a patient with a partial “de novo” duplication in the distal segment of the long arm of chromosome 4 (q31, q35), in association with Robertsonian translocation between chromosomes 14 and 21. This association has not been described previously. In the 4q duplication, the relationship between the phenotype and the parts of the duplicated segment is not well defined, although it seems clear that the renal anomalies and/or thumbs abnormalities are a characteristic manifestation. We have reviewed the literature and, of the cases previously described with trisomy q31-35, we came to the conclusion that this region of chromosome 4 may also be involved in constituting the “Syndrome of partial trisomy 4q” or Auriculo-acro-renal Syndrome”.
Partial trisomy 4q and monosomy 9p in a girl with severe mental retardation, multiple anomalies and congenital hypoglycaemia
2007, Pediatria Polska
Unbalanced chromosomal aberrations are one of the most common causes of mental retardation and congenital defects. We analized genotype-phenotype correlations in a girl with dysmorphism, heart defect and hypoglycaemic attacks. The proband was born at term, after 2 years childless marriage, her birth weight was 2880 g. After birth, her phenotype was described as abnormal. She had microcephaly, scull with protruding sutures, narrow, short palpebral fissures, hypoplastic nose, hypoplastic nails, singular crease on right hand, clinodactyly of V fingers, excessive hair covering her face, shoulders and thighs, heart defect and vesico-uretheral reflux. She was also diagnosed as having hypothyroidism and hypoglycaemic attacks accompanied by seizures. Cytogenetic studies and FISH with WCP4 and WCP9 probes revealed an unbalanced karyotype: 46,XX,der(9)t(4;9)(q21;p22),9ph. The proband's mother's karyotype was normal female with pericentric inversion 9. The proband's father refused consent for cytogenetic studies.
Niezrównoważone aberracje chromosomowe stanowią jedną z głównych przyczyn niepełnosprawności intelektualnej i wad wrodzonych. Analizowaliśmy korelacje genotyp-fenotyp u dziewczynki z dysmorfią, wadą serca i napadami hipoglikemii. Probandka urodziła się o czasie, po 2 latach trwania małżeństwa, z urodzeniową masą ciała 2880 g. Po urodzeniu stwierdzono nieprawidłowy fenotyp. Opisywano małogłowie, nieregularną czaszkę, wąskie, krótkie szpary powiekowe, hipoplastyczny nos, hipoplastyczne paznokcie, pojedynczą bruzdę dłoni prawej, klinodaktylię palców V, nadmierne owłosienie pokrywające twarz, ramiona i uda, wadę serca i refluks pęcherzowo-moczowodowy. U pacjentki rozpoznano również niedoczynność tarczycy oraz napady hipoglikemiczne z drgawkami. W badaniu cytogenetycznym potwierdzonym metodą FISH z sondami WCP4 i WCP9, stwierdzono obecność niezrównoważonego kariotypu 46,XX,der(9)t(4;9)(q21;p22),9ph. U matki pacjentki stwierdzono kariotyp prawidłowy żeński z pericentriczną inwersją chromosomu 9. Ojciec dziewczynki nie wyraził zgody na badanie cytogenetyczne.
Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly
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Case reportLarge duplication 4q25–q34 with mild clinical effect

Abstract

Introduction

Section snippets

Clinical report

Cytogenetic analysis

Results

Discussion

Ann. Genet.

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

Am. J. Med. Genet.

Familial tandem duplication of bands q31.1 to q32.3 on chromosome 4 with mild phenotypic effect

Am. J. Med. Genet.

Comparison of comparative genomic hybridization with conventional karyotype and classical fluorescence in situ hybridization for prenatal and postnatal diagnosis of unbalanced chromosome abnormalities

Ann. Genet.

Case report
Large duplication 4q25–q34 with mild clinical effect