Article Text

Download PDFPDF

Molecular characterisation of a 3.5 Mb interstitial 14q deletion in a child with several phenotypic anomalies
  1. E Petek1,
  2. B Plecko-Startinig2,
  3. C Windpassinger1,
  4. H Egger1,
  5. K Wagner1,
  6. P M Kroisel1
  1. 1Institute of Medical Biology and Human Genetics, Karl-Franzens University of Graz, Graz, Austria
  2. 2Department of Paediatrics, University of Graz, Graz, Austria
  1. Correspondence to:
 Dr E Petek, University of Graz, Institute of Medical Biology and Human Genetics, Harrachgasse 21/8, A-8010 Graz, Austria; 

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Interstitial deletions of the long arm of chromosome 14 are infrequent. Molecular and clinical studies on patients with deletions involving 14q11.2-q21 have recently been reported.1 Most of these deletion patients share common clinical signs, such as midline defects of the central nervous system, feeding problems, growth abnormalities, hypotonia, developmental delay, mental retardation, and craniofacial anomalies.1 Here we present the phenotypic, cytogenetic, and molecular genetic findings of a 2½12 year old boy with a 14q12-q13.1 deletion. To our knowledge this is the second case described of a patient with a deletion of less than 3.5 Mb within chromosome bands 14q12-q13.1. Using the genomic sequence between markers D14S1060 and D14S286, we have constructed a transcription map of the genomic interval deleted in our patient.


Our proband (fig 1) is the 40 week product of a second, uncomplicated pregnancy and delivery. Maternal age was 27 years. Birth weight was 4435 g (>90th centile), length 55 cm (>90th centile), and head circumference 34 cm (10th-25th centile). Apgar score was 7/9/10. The neonatal period was complicated by pneumonia, treated with parenteral antibiotic therapy over 10 days. Besides relative microcephaly, hypertelorism, epicanthic folds, a long and flat philtrum, hypodontia, laterally placed, hypoplastic mamillae, second degree hypospadias, bifid scrotum, and bilateral cryptorchidism were noticed. Cranial ultrasound was normal; ultrasound of the kidneys and pelvic region showed bilateral second degree hydronephrosis, and both testes were visible in the inguinal region. Screening for connatal infections (toxoplasmosis, rubella, cytomegalovirus, and parvovirus B19) was negative. Psychomotor development was severely impaired from early infancy. Lack of vision was evident at 3 months and, apart from head control, no gain of motor milestones or social contact was achieved until the age of 29 months. Muscle tone of the trunk was decreased while it was increased and dystonic in the upper and lower extremities with exaggerated deep tendon reflexes.

Figure 1

(A) Frontal, (B) lateral, and (C) total view of the proband.

During the second year of life, high arched, bushy eyebrows and plantar hyperkeratosis developed. Weight (11.2 kg) and length (89 cm) were on the 3rd and 10th-25th centile at the age of 29 months, respectively, while the head circumference, 43.9 cm, was far below the 3rd centile (fig 1). Fundoscopy at the age of 4 months showed bilateral optic atrophy. Normal bilateral hearing was assessed using a commercial infant hearing screening device (ALGO, Natus Medical, Foster City, CA). Cranial MRI at the age of 9 months showed no signs of cerebral malformation but did show reduced brain mass and bilaterally dilated ventricles and widened subarachnoidal spaces. Myelination was moderately delayed for his age. EEG, performed at the age of 23 months, showed low voltage (20–100 μV), mildly slowed background activity without epileptic discharges.

Key points

  • By using region specific BAC clones for FISH analysis and polymorphic markers, we characterised a 3.5 Mb interstitial 14q12-q13.1 deletion in a 2½12 year old boy with microcephaly, psychomotor retardation, bilateral optic atrophy, hypodontia, and several minor dysmorphic features. Marker analyses showed that the derivative chromosome 14 is of maternal origin.

  • We have also generated a transcription map of the contiguous genomic interval deleted in our patient, linking the regions near markers D14S1060 and D14S286.

  • Several known genes, including TITF1, PAX9, and MIPOL1, were identified in this genomic segment and are thus potential candidates for some of the phenotypic features observed in our patient.


G banded metaphase chromosomes from lymphocyte culture of the patient showed an apparent de novo interstitial deletion on the long arm of chromosome 14 in 50 metaphases analysed. His karyotype was interpreted as 46,XX, del(14)(q12q13.1) (fig 2). To exclude translocation of the deleted segment to another chromosome, we performed fluorescence in situ hybridisation (FISH) with a commercial painting probe for chromosome 14 (VYSIS Inc, Illinois, USA; data not shown).

Figure 2

Partial G and R banded high resolution karyotype of the normal and the derivative chromosomes 14.

In order to define the breakpoints of the deletion on the long arm of chromosome 14 in more detail, we hybridised digoxigenin labelled DOP-PCR products of eight bacterial artificial chromosomes (BACs RP11-1078I14 (GenBank accession No AL161851), RP11-1007I4 (AL358340), RP11-26M6 (B84609, B84610), RP11-81F13 (AL162464), RP11-1149E6 (AQ749750, AQ749839), RP11-410J3 (AQ549717, AQ535528), RP11-356O6 (AL121790), RP11-91H1 (AQ283374, AQ283377)) to metaphase spreads of the patient.2 Of eight BAC clones analysed, BAC clones RP11-26M6 and RP11-81F13 showed signals on only one copy of chromosome 14q (fig 3A). The signal for the remaining six BAC clones was detected on both copies of chromosome 14q (fig 3B).

Figure 3

Fluorescence in situ hybridisation using digoxigenin labelled DOP-PCR products of (A) BAC RP11-26M6 (only one signal on normal chromosome 14), (B) BAC RP11-1007I4 (one signal on normal chromosome 14 and one signal on der(14)). The normal chromosome 14 is indicated by an arrowhead and the der(14) is indicated by an arrow.

Genomic DNA was extracted from peripheral blood lymphocytes using standard techniques.3 Genotyping of the proband and his parents was performed with chromosome sequence tagged site (STS) microsatellite markers D14S1041, D14S275, D14S80, D14S1042, D14S262, D14S1021, D14S1060, D14S70, D14S1049, D14S988, D14S253, D14S1017, D14S69, D14S75, D14S286, and D14S1039 by PCR amplification. This analysis showed that the deletion of chromosome 14q in this patient was maternal in origin. STS markers D14S70, D14S1049, D14S988, D14S253, D14S1017, D14S69, and D14S75, all six within the region of the deletion, showed one paternal allele but no maternal allele (data not shown). Markers D14S1041 and D14S1039 were uninformative.

To identify clinical features with a genetic basis or genetic component mapped within the deleted region in 14q we constructed an annotated gene map of the interval D14S1060-D14S286. The April 2002 freeze of the Genome Browser of the UC Santa Cruz ( showed 20 “Reference Sequence genes (known genes)” in the genomic region of the deletion that corresponds to mouse chromosome 12. By a combination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped five additional transcripts (PSMA6, DKFZp566D133, KIAA0884, MIPOL1, and LOC115669) within this interval (table 1, fig 4). Many of these are novel or hypothetical proteins and further investigation is needed to determine if any of these sequences are actively expressed and their potential contribution to the phenotype of our 14q deletion patient. Besides these transcripts, the large number of spliced expressed sequence tags (ESTs) in this region will probably lead to the identification of additional genes, not yet characterised.

Table 1

Genes mapped to the interval between markers D14S1060 and D14S286

Figure 4

Transcription map of the genomic interval between markers D14S1060 and D14S286 on human chromosome 14q. The proximal and distal breakpoint region of the der(14) in our patient is shown. The deleted interval reported by Breedveld et al7 is also shown. Genes are indicated by arrows or arrowheads. Markers and BAC clones deleted on the der(14) in our patient are indicated by an asterisk.

Mutations responsible for dominant inherited clinical features are reported for PAX9 (hypodontia, OMIM 106600),5MIPLO1 (mirror image polydactyly of hands and feet, OMIM 135750),6 and TITF1 (benign hereditary chorea, OMIM 118700).7 Whereas hypodontia can also be found in our patient, no hand and foot abnormality was diagnosed in the present case or in the previously published 14q deletion patients.1 Gene mutations and breakpoint junctions, however, cannot always be used to explain affected phenotypes in deletion cases. In addition, MIPLO1 is located several kbs distal to the deleted segment in our patient. Haploinsufficiency for the MIPOL1 gene was suspected to be responsible for limb anomalies owing to its disruption in a t(2;14) translocation case.6 Other genes close to the breakpoints on chromosomes 2 and 14, like the death box gene DDX1 (GenBank accession No X70649) and the neuroblastoma amplified protein gene NAG (GenBank accession No NM015909), both located proximal to the breakpoint on 2p23.3, and the PAX9 gene on 14q13 cannot formally be excluded. The locus on 14q13 is supported by an additional translocation patient with mesomelic bone dysplasia (case 9 of Kamnasaran et al1).

Psychomotor retardation and microcephaly are common characteristics in both our case and the reported cases with larger 14q deletions.1 Autistic-like behaviour and visual problems, such as cortical blindness, have also been reported in most of them. In order to identify potential candidate genes, we were especially interested in genes that may play a role in neurodevelopment. Recently, Breedveld et al7 identified mutations in the gene encoding the thyroid transcription factor 1 protein leading to benign hereditary chorea (BHC). Knockout studies showed that this gene is involved in the differentiation of the striatum in the developing brain.8 In one of their BHC families, two subjects in two subsequent generations could be identified as carriers of a 1.2 Mb microdeletion harbouring five transcripts (MBIP, TITF1, NKX2.8, PAX9, and SLC25A21; table 1, fig 4). Since patients with this microdeletion, which represents the telomeric segment of the deletion described here, do not show microcephaly, it is possible to conclude that the putative locus for this form of microcephaly maps more proximally. In this region, genes expressed in the developing brain such as genes from the KIAA library are especially promising candidates. However, variable expressivity of genes within the 1.2 Mb microdeletion7 cannot formally be excluded as a cause of microcephaly.

In conclusion, we have reported a patient with an interstitial 14q deletion of less than 3.5 Mb and generated a contiguous transcription map of this region. In addition, we were able to identify candidate genes for the features found in our patient that warrant further functional investigations.


We thank the family for all their help in this study. This research was supported by grant 9522 from the Oesterreichischen Nationalbank to EP.