A 2.3Mb deletion of 17q24.2-q24.3 associated with 'Carney Complex plus'

We present a 12-year-old with ade novo interstitial deletion of approximately 2.3 Mb in chromosome band 17q24.2–q24.3, which was identified by array CGH. The most characteristic features in this case are posterior laryngeal cleft and the presence of numerous freckles and lentigines in childhood. Growth restriction, microcephaly and moderate mental retardation are also prominent features but are frequently seen with other chromosomal anomalies. The microdeletion causes haploinsufficiency of PRKAR1A (protein kinase, cAMP-dependent, regulatory 1α), which is known to cause Carney Complex but this diagnosis alone does not account for all of her problems and she therefore has ‘Carney Complex plus’. This report illustrates the practical benefits associated with a clear cytogenetic diagnosis, as regular endocrinological and cardiac screening is required.     

A 400kb duplication, 2.4Mb triplication and 130kb duplication of 9q34.3 in a patient with severe mental retardation

The presence of a duplication as well as a triplication in one chromosome is a rare rearrangement and not easy to distinguish with routine chromosomal analysis. Recent developments in array technologies, however, not only allow screening of the whole genome at a higher resolution, but also make it possible to characterize complex chromosomal rearrangements in more detail. Here we report a molecular cytogenetic analysis of a 16-year old female with severe mental retardation and an abnormality at the end of the long arm of chromosome 9. Subtelomeric multiplex ligation-dependent probe amplification (MLPA) analysis revealed that the extra material originated from the telomeric end of chromosome 9q. Fine mapping using a high-resolution single nucleotide polymorphism (SNP) array detected a duplication of approximately 400kb upstream of a approximately 2.4Mb triplication followed by a duplication of approximately 130kb of chromosome 9q34.3. This study underscores the value of combining conventional karyotyping with novel array technologies to unravel complex chromosomal alterations in order to study their phenotypic impact.     

Familial mental retardation associated with balanced chromosome rearrangement rcp t(8;11)(q24.3;p15.1).

We report three sisters and their father with a reciprocal balanced translocation, rcp t(8;11)(q24.3;p15.1) and the same abnormal phenotypes, including mental retardation, growth disturbance, and amblyopia. It is considered that the abnormal phenotypes in our four cases might result from a tiny deletion or gene mutation at the breakpoints in 8q or 11p or both. Our cases showed no resemblance, apart from mental retardation, to Langer-Giedion syndrome, which is caused by the deletion of 8q23.3 and 8q24. Furthermore, our patients did not have the cardinal features of Beckwith-Wiedermann syndrome or WAGR which are caused by deletion of 11p. It is suggested that the amblyopia in our four cases might have resulted from the breakpoints at 11p15.1.     

A de novo 8q22.2-24.3 duplication in a patient with mild phenotype

We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8q+, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 → qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome.     

A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.     

9 Mb deletion including chromosome band 3q24 associated with unsuspicious facial gestalt, persistent ductus omphaloentericus, mild mental retardation and tic

9 Mb deletion including chromosome band 3q24 associated with unsuspicious facial gestalt, persistent ductus omphaloentericus, mild mental retardation and tic.     

A 15Mb duplication of 6q24.1-q25.3 associated with typical but milder features of the duplication 6q syndrome

We report on a female patient carrying a de novo 15Mb duplication of 6q24.1-q25.3 detected by conventional karyotyping and fine-mapped by molecular karyotyping with a 250K SNP array. Pure interstitial duplications of 6q are rarely reported in the literature and none of them exactly mapped by array technique so far. Our patient shows typical aspects of the "duplication 6q" syndrome such as hypertelorism, downslanting palpebral fissures, carp shaped mouth and joint contractures, but milder mental retardation and no growth retardation.     

A 6Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features

High-resolution analyses of complex chromosome rearrangements (CCR) have demonstrated in individuals with abnormal phenotypes that not all seemingly balanced CCRs based on G-banding are completely balanced at breakpoint level. Here we report on an apparently balanced de novo CCR involving chromosomes 2, 3 and 5 present in a 6-month-old girl. She was referred for genetic evaluation because of severe psychomotor retardation, distinctive dysmorphic features and microcephaly. A 1Mb resolution array-CGH analysis of DNA from the patient revealed a deletion of about 6Mb for chromosome 2. FISH analysis showed that the deletion interval found in band 2q22 mapped at the translocation breakpoint, and that the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrome, is located within the deletion interval. To our knowledge this is the first case of a complex chromosomal rearrangement associated with Mowat-Wilson syndrome. Our data illustrate the important role for high-resolution investigation of apparently balanced chromosome rearrangements in patients with unexplained psychomotor retardation and/or other clinical features, and should contribute to our understanding of the mechanisms involved in chromosome rearrangement.     

6.7 Mb interstitial duplication in chromosome band 11q24.2q25 associated with infertility, minor dysmorphic features and normal psychomotor development

We report on a healthy man with high normal intelligence, minor dysmorphic features and infertility due to hypogonadism and azoospermia. Cytogenetic analysis showed a 6.7 Mb duplication in chromosome band 11q24.2q25, which could be confirmed with FISH and molecular karyotyping using an Affymetrix GeneChip Human Mapping 250 K Nsp SNP array.     

Deletion 2q36.2q36.3 with multiple renal cysts and severe mental retardation

Interstitial 2q36 deletion is a rare event. We report on a patient with a de novo del(2)(q36.2q36.3) interstitial deletion of the long arm of chromosome 2 diagnosed by classical banding. The phenotype comprised facial dysmorphism, enlarged kidneys with multiple renal cysts, abnormal minora labia, asymmetric lower limbs with dysplastic patella, and severe mental retardation. By physical mapping, using array-comparative genomic hybridisation (CGH) confirmed by Fluorescent In Situ Hybridisation (FISH), the breakpoints of the deletion were mapped and the size of the deletions was measured: 5.61 ± 0.19 Mb. A skin biopsy was analysed using electronic microscopy showing an alteration of the structure and organisation of the dermal and peri-neuronal basement membrane. The relation between the phenotype and the deletion of both COL4A4 and COL4A3 genes, located in 2q36.3 loci, as well as the disruption of TRIP12 were discussed.     

Familial 1.1 Mb deletion in chromosome Xq22.1 associated with mental retardation and behavioural disorders in female patients

We report on a 7-year-old girl with severe mental retardation (MR), autism, micro-brachycephaly, generalized muscle hypotonia with distal hypotrophy of lower limbs, scoliosis and facial dysmorphisms. Array-CGH analysis identified a 1.1 Mb deletion of chromosome Xq22.1. Further analysis demonstrated that the deletion was inherited from her mother who showed mild MR, short stature, brachycephaly, epilepsy and a Borderline Personality Disorder. Microsatellite segregation analysis revealed that the rearrangement arose de novo in the mother on the paternal X chromosome. The deleted Xq22.1 region contains part of the NXF gene cluster which is involved in mRNA nuclear export and metabolism. Among them, the NXF5 gene has already been linked to mental retardation whereas NXF2 protein has been recently found to be partner of FMRP in regulating Nxf1 mRNA stability in neuronal cells. The dosage imbalance of NXF5 and NXF2 genes may explain the severe phenotype in our patient.     

Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features

The regions near telomeres of human chromosomes are gene rich. Chromosome subtelomere rearrangements occur with a frequency of 7-10% in children with mild-to-moderate mental retardation (MR) and approximately 50% of cases are familial. Clinical investigation of subtelomere rearrangements is now prompted by fluorescence in situ hybridization (FISH) analysis using specific DNA probes from all relevant chromosome ends. In our study, 40 children were selected for subtelomere assay using either the Chromophore Multiprobe-T Cytocell device or the VYSIS TelVision probes. Inclusion criteria were: developmental delay or MR; a normal 550 G-band karyotype; FRAXA negative; and at least one other clinical criterion. Exclusion criteria included an identified genetic or environmental diagnosis. Of the 40 patients analysed, four (10%) were found to have subtelomere rearrangements. Three of 40 (7.5%) were found to have an unbalanced subtelomere rearrangement and one of 40 (2.5%) was found to have an apparently normal variant subtelomere deletion. The first of the three with an unbalanced karyotype was the result of a familial translocation, the second was a de novo finding, and the origin of the third could not be determined. The subtelomere FISH assay detected almost twice the frequency of unbalanced karyotypes as those detected by 550 G-banding in our cytogenetics laboratory (4.7%). In addition, subtelomere screening was eight times more likely than fragile X screening in our DNA laboratory (1%) to detect genetic abnormalities in mentally handicapped individuals. Our findings support the view that screening for subtelomere rearrangements has a greater positive yield than other commonly used genetic investigations and, if cost and resources permit, should be the next diagnostic test of choice in a child with unexplained MR/dysmorphisms and a normal 550 G-band karyotype.     

A novel 1.4 Mb de novo microdeletion of chromosome 1q21.3 in a child with microcephaly,dysmorphic features and mental retardation

A 2.5 years old girl presented with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. About 1 Mb deletion in the chromosomal region 1q21.3 was identified using BAC array CGH analysis. The parental follow up FISH analysis was normal. Further study of the deletion using a 244K oligo-array of Agilent Technologies Inc., Santa Clara, CA, USA defined the deleted region to span about 1.4 Mb with approximate genomic location chr1:152,511,593-153,993,103 (NCBI genome build 36). This is a novel deletion, not reported to-date. Larger proximal 1q deletions that were previously reported typically included microcephaly, mental retardation and multiple congenital anomalies. The deleted region reported here includes at least 30 coding genes. Among them of interest is a three-gene cluster of the ephrin gene family (EFNA1, EFNA3 and EFNA4). This is a group of receptor protein-tyrosine kinase type genes with presumed, but not completely characterized function in nervous system development.     

A duplication/deficient X chromosome in a girl with mental retardation and dysmorphic features.

A structurally abnormal X chromosome was found in a nine year old girl with mild mental retardation and dysmorphic features. Subsequent clinical examination at 18 years of age showed tall stature and gonadal dysgenesis. Re-examination of her karyotype using a variety of banding techniques on prometaphase chromosomes allowed the identification of the abnormal chromosome as a duplication/deficient X chromosome, 46,Xder X(pter----q28::p11.2----pter). The clinical features are discussed in terms of karyotype/phenotype correlation.     

A novel case of unilateral blepharophimosis syndrome and mental retardation associated with de novo trisomy for chromosome 3q.

We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features include microcephaly, high, narrow forehead, short stubby fingers, and adduction of the right first toe. Cytogenetic analysis showed an unbalanced karyotype consisting of 46,XX,add(7)(q+) that was de novo in origin. Fluorescence in situ hybridisation (FISH) using microdissected library probe pools from chromosomes 1,2,3,7, and 3q26-qter showed that the additional material on 7q was derived from the distal end of the long arm of chromosome 3. Our results indicate that the patient had an unbalanced translocation, 46,XX,der(7)t(3;7)(q26-qter;q+) which resulted in trisomy for distal 3q. All currently reported cases of BPES (blepharophimosis-ptosis-epicanthus inversus syndrome) with associated cytogenetic abnormalities show interstitial deletions or balanced translocations involving 3q22-q23 or 3p25.3. Our patient shares similar features to BPES, except for the unilateral ptosis and absence of epicanthus inversus. It is possible that our patient has a contiguous gene defect including at least one locus for a type of blepharophimosis, further suggesting that multiple loci exist for eyelid development.     

Two cases of an abnormal short arm of chromosome 8 (8p+) associated with mental retardation

Morphologically similar chromosome anomalies, 8p+, were found in two inmates of an institution for the mentally retarded. Analysis of the G-and R-banding patterns showed that the first subject had a duplication of region p2 of chromosome 8; the second subject had an insertion of an unidentified chromosome segment at 8p11. Both subjects were severely mentally retarded. The physical malformations were more severe in the second subject than in the first, who had only minor signs. The dermatoglyphics are recorded.     

Autism, language delay and mental retardation in a patient with 7q11 duplication

Background

Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams–Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams–Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay.

Objective and Methods

In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation‐dependent probe amplification.

Results

We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features.

Conclusion

We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.     

An atypical 0.8 Mb inherited duplication of 22q11.2 associated with psychomotor impairment

Microduplications 22q11.2 have been recently characterized as a new genomic duplication syndrome showing an extremely variable phenotype ranging from normal or mild learning disability to multiple congenital defects and sharing some overlapping features with DiGeorge/velocardiofacial syndrome (DGS/VCFS), including heart defects, urogenital abnormalities and velopharyngeal insufficiency.