CALL gene is haploinsufficient in a 3p- syndrome patient.

The 3p- syndrome results from deletion of a terminal segment of the short arm of one chromosome 3 (3p25-->pter), and is characterized by multiple congenital anomalies and mental retardation. Due to its variable expression, it is assumed this disorder is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to discover genes contributing to mental defects in 3p- syndrome, we determined whether the CALL gene, mapped to 3p26.1 and coding for a neural recognition molecule, is deleted in a boy with this disorder. We found that the break in this patient is distal to the VHL gene, removing D3S18 and the CALL loci. The deletion of one copy of the CALL gene might be responsible for mental defects in patients with 3p- syndrome. Am. J. Med. Genet. 86:482-485, 1999. Published 1999 Wiley-Liss, Inc.     

Molecular characterization of a patient with 3p deletion syndrome and a review of the literature

3p deletion syndrome is a rare disorder involving developmental delay, dysmorphic physical features, and growth retardation. Molecular mapping of several cases in the literature have identified a critical region on chromosome 3p26. We present a child patient with characteristic features of 3p deletion syndrome and a de novo unbalanced translocation involving chromosomes 3 and 13. Fine mapping of this rearrangement using fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) revealed an unbalanced abnormality including a 4.5 Mb terminal deletion of chromosome 3p, telomeric to ITPR1 on 3p26.2, which was not previously identified with routine cytogenetic analysis. In addition, these investigations confirmed and refined the boundaries of a 26.5 Mb deletion of chromosome 13. This study confirms the minimal candidate region for 3p deletion syndrome, provides further evidence implicating haploinsufficiency of CNTN4 in the disorder, and demonstrates the utility of high-resolution investigations of rare chromosomal rearrangements.     

Molecular characterization and clinical features of a patient with an interstitial deletion of 3p25.3-p26.1

Distal chromosome 3p deletions (3p- syndrome) are associated with various developmental defects. The majority of cases have a terminal deletion of the short arm of chromosome 3 with loss of either the maternal or the paternal copy. A girl with an interstitial molecularly characterized 1.6?Mb deletion in cytoband 3p25.3-26.1 of the paternal chromosome 3 is presented. To our knowledge, she possesses the smallest deletion that has ever been reported for a patient with a clinical phenotype in accordance with the 3p- syndrome. The boundaries of the deletion lies within nearly all previously reported terminal deletions causing this syndrome. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient as regards the congenital heart defect, autistic behavior and mental retardation (CAV3, OXTR, and SRGAP3/MEGAP, respectively) are discussed in context of the clinical features.     

Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.     

A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy

Chromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene −/− mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome. Received: March 4, 2002 / Accepted: July 7, 2002     

Trisomy 18 phenotype in a patient with an isopseudodicentric 18 chromosome.

We report a female patient with a typical trisomy 18 phenotype who has a 46,XX, -18, +isopseudodic(18)(p11) karotype. The lack of features of the 18p- syndrome suggests that a significant amount of short arm material is present and that the Turner-like features associated with 18p- may be determined by monosomy for 18p11. The phenotype-genotype correlations in abnormalities affecting chromosome 18 are reviewed.     

Heterozygous deletion of CHL1 gene: Detailed array-CGH and clinical characterization of a new case and review of the literature

CHL1 gene maps at 3p26.3 and encodes a cell adhesion molecule of the immunoglobulin superfamily highly expressed in the brain. CHL1 regulates neuronal migration and neurite overgrowth in the developing brain, while in mature neurons it accumulates in the axonal membrane and regulates synapse function via the clathrin-dependent pathways. To our knowledge, to date only three familial cases presenting heterozygous deletion of chromosome 3 at band p26.3, including only the CHL1 gene, have been reported. All the patients presented cognitive impairment characterized by learning and language difficulties. Here, we describe a six-year-old boy in which array-CGH analysis disclosed a terminal 3p26.3 deletion. The deletion was transmitted from his normal mother and included only the CHL1 gene. Our patient presented microcephaly, short stature, mild mental retardation, learning and language delay, and strabismus.In our study we compare the phenotypic and molecular cytogenetic features of CHL1 gene deletion cases. Verbal function developmental delay seems to be a common key finding. The concomitance of the genetic and phenotypic alterations could be a good evidence of a new emerging syndrome associated with the deletion of CHL1 gene alone, although the identification of new cases is required.     

Genotype-phenotype correlation of 5p- syndrome: pitfall of diagnosis

To clarify the genotype–phenotype correlation of 5p- syndrome, FISH analyses were performed for six patients by using a series of probes spanning 5p13.1–p15.33. Genotypically, break points of deletion were quite different. Three of the six patients were diagnosed as interstitial deletion on chromosome 5p by G-banding method and FISH analysis; however, all of them proved to be entire distal deletions of 5p caused by unbalanced chromosomal translocations. Furthermore, one 5p- syndrome patient was diagnosed only by the FISH analysis using a single probe but not by ordinary chromosomal analyses. Therefore, when ordinary chromosomal analysis cannot detect any deletion in a patient who is phenotypically suspected of 5p- syndrome, multiple FISH analysis or parental chromosomal analysis would be needed for correct diagnosis. Interestingly, one patient with terminal deletion between 5p15.31-pter lacks mental retardation and cat-like crying, indicating that this region might not be responsible for those cardinal features of 5p- syndrome. Further studies on genotype–phenotype correlation will help us better understand 5p- syndrome and also determine functional mapping of the 5p region.     

Towards mapping phenotypical traits in 18p- syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

Molecular karyotyping holds the promise of improving genotype-phenotype correlations for frequent chromosome conditions such as the 18p- syndrome. In spite of more than 150 reported cases with deletions in 18p, no reliable phenotype map for the characteristic clinical findings such as mental retardation, post-natal growth retardation and typical facial features has been established yet. Here, we report on four patients with partial monosomy 18p of different sizes owing to unbalanced translocations that were thoroughly characterised clinically and by molecular karyotyping. One patient had a terminal deletion of 1.6 Mb in 18p and a trisomy of 8q24.23-qter as determined by array-based comparative genomic hybridisation and large insert clone fluorescent in situ hybridisation. In two sibs and a fourth patient, cytogenetic and molecular-cytogenetic analyses showed the terminal deletions in 18p (8.0 and 13.84 Mb, respectively) to be accompanied by partial trisomies of 20p. Literature analyses of typical phenotypic features of 18p-, 8q+ and 20p+ syndromes allowed the attribution of clinical findings in our patients to the respective chromosomal aberration. Based on these data, we propose a phenotype map for several clinical features of the 18p- syndrome: Round face was tentatively mapped to the distal 1.6 Mb of 18p; post-natal growth retardation and seizures to the distal 8 Mb and ptosis and short neck to the proximal half of 18p.     

CALL gene is haploinsufficient in a 3p− syndrome patient

The 3p− syndrome results from deletion of a terminal segment of the short arm of one chromosome 3 (3p25→pter), and is characterized by multiple congenital anomalies and mental retardation. Due to its variable expression, it is assumed this disorder is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to discover genes contributing to mental defects in 3p− syndrome, we determined whether the CALL gene, mapped to 3p26.1 and coding for a neural recognition molecule, is deleted in a boy with this disorder. We found that the break in this patient is distal to the VHL gene, removing D3S18 and the CALL loci. The deletion of one copy of the CALL gene might be responsible for mental defects in patients with 3p− syndrome. Am. J. Med. Genet. 86:482–485, 1999. Published 1999 Wiley-Liss, Inc.     

Kallmann syndrome in a patient with congenital spherocytosis and an interstitial 8p11.2 deletion

We describe the hitherto smallest interstitial 8p11.2 deletion in a patient with congenital spherocytosis, dysmorphic features, and growth delay in association with hypogonadotropic hypogonadism and anosmia. The latter features are characteristic for Kallmann syndrome. In contrast to the previously reported patients with 8p deletions, the present patient showed normal intelligence. Congenital spherocytosis is one of the most common hereditary hemolytic anemias. One of the three loci for congenital spherocytosis was assigned to chromosome 8p (located between 8p11.1 and 8p21) and mutations in or loss of the ankyrin-1 gene (ANK1) were identified. Molecular analysis confirmed the de novo loss of ANK1 in our patient. Kallmann syndrome, which is characterized by hypogonadotropic hypogonadism and anosmia, can be X-linked, autosomal dominant, or autosomal recessive. So far only the X-linked KAL1 gene has been identified. The present finding suggests an autosomal locus for Kallmann syndrome at 8p11.2. The simultaneous occurrence of congenital spherocytosis, Kallmann syndrome phenotype, dysmorphic features, and growth delay in this patient points to a new contiguous gene syndrome.     

Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome

Deletion 3p syndrome is associated with characteristic facial features, growth failure, and mental retardation. Typically, individuals with deletion 3p syndrome have terminal deletions that result in loss of material from 3p25 to 3pter. We present a child with a clinical phenotype consistent with deletion 3p syndrome (ptosis, microcephaly, growth retardation, and developmental delay) and a subtle interstitial deletion in the distal portion of the short arm of chromosome 3, del(3)(p25.3p26.2). Fluorescence in situ hybridization (FISH) studies using 3p subtelomeric probes confirmed the terminal region of chromosome 3 was present. Sequence tagged sites (STS)-linked BAC clones mapping to chromosomal region 3p25-p26 were used to characterize the interstitial deletion by FISH. The results indicate the deletion is within a region of approximately 4.5 Mb between STS markers D3S3630 and D3S1304. This interstitial deletion lies within all previously reported terminal deletions in deletion 3p syndrome individuals, and represents the smallest reported deletion associated with deletion 3p syndrome. Characterization of the deletion may help identify genes important to growth and development that contribute to the deletion 3p syndrome phenotype when present in a hemizygous state.     

Chromosome 18 aberrations and epilepsy: a review

Epilepsy is commonly observed in patients with chromosomal aberrations. We evaluated epilepsy and electroencephalographic (EEG) features in a group of patients carrying aberrations of chromosome 18. Fourteen patients were recruited: five with an 18p deletion syndrome (18pDS); six with an 18q deletion syndrome (18qDS); two with trisomy 18p syndrome; and one with a 45,XY,t(17-18) (cen-q11.2) karyotype. Patients with 18pDS had neither epilepsy nor EEG anomalies; four patients with 18qDS had epilepsy with partial seizures occurring during infancy or early childhood. Partial seizures were also present in both patients with trisomy 18p. By contrast, mixed seizures were observed in the patient carrying a translocation between chromosomes 17 and 18. Our data and a re-evaluation of the literature suggest that epilepsy is infrequent in patients with 18pDS. Conversely, partial seizures and focal EEG anomalies may be observed in those with patients with 18qDS. Our observations suggest that the haplo-insufficiency of genes located on the long arm of chromosome 18 is more likely to be associated with epilepsy, than is haplo-insufficiency of genes located on the short arm. While further EEG/clinical investigations are needed to validate these observations, this study indicates a possible relationship between chromosome 18 genes and epilepsy.     

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.     

Recombinant 4 syndrome due to an unbalanced pericentric inversion of chromosome 4

An informative patient with a MCA/MR syndrome consisting of developmental delay, prenatal onset growth delay, microcephaly, distinctive face, iris coloboma, and a congenital heart defect was found, on chromosome analysis, to have the following complement: 46,XY,rec(4) dup(4p) inv(4)(p14q35.1) mat. He has a partial 4p trisomy/distal 4q deletion due to an unbalanced pericentric inversion inherited from his mother. Dup (4p) trisomy was originally described by Wilson et al. [1970: Am J Hum Genet 22:679-690] in a similar case with the same chromosome 4 inversion. To date, at least 85 cases of dup (4p) syndrome have been published, mostly due to unbalanced translocations. Recent articles suggest that the phenotype is hard to recognize clinically due to the lack of specificity of findings. In contrast, 4p trisomy due to an unbalanced pericentric inversion of chromosome 4(p14q35), i.e., the recombinant 4 syndrome observed in our patient, appears to be a discrete entity with relatively consistent features. In total there are four other kindreds described in the literature with this inversion, and the phenotype seems recognizable. Thus, we suggest that recombinant 4 syndrome is a discrete entity among 4p trisomy patients.     

A microduplication of CBP in a patient with mental retardation and a congenital heart defect

Rubinstein-Taybi syndrome is a well-characterized genetic syndrome caused by haploinsufficiency of CBP in a majority of individuals. In 10% of cases a microdeletion in 16p13.3 affecting CBP is detected. We report on a patient with a de novo 345-480 kb micro-duplication the region, encompassing only CBP and TRAP1. This boy presented with various minor physical anomalies, moderate mental retardation, and an atrial septal defect, but none of the other typical characteristics of the Rubinstein-Taybi syndrome, such as the broad thumbs and first toes or facial characteristics. This finding implicates CBP as one of the causative genes for the trisomy 16p13 syndrome, and indicates this is a contiguous gene syndrome.     

Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components

Hepatoblastoma (HB) is the most common liver tumor in childhood and differs in its environmental risk factors and genetic background from hepatocellular carcinoma. HB is associated with inherited conditions such as familial adenomatous polyposis and Beckwith-Wiedemann syndrome, suggesting the importance of genetic abnormalities in the pathogenesis and progression of this disease. It has a very polymorphous morphology. A diverse range of cytogenetic alterations has been reported to date, the most frequent being trisomy 2 and trisomy 20. Thirty-five HB specimens from 31 patients (22 purely epithelial, 4 purely mesenchymal, 9 mixed) were examined by comparative genomic hybridization (CGH), a technique that enables us to screen the entire tumor genome for genetic losses and gains. Our aims were as follows: (1) to characterize chromosome abnormalities that appear in this tumor and (2) to identify possible differences between different histologic subtypes of HB. We found significant gains of genetic material, with very little difference in the number and type of alterations between the different histologic components of HB. The most frequent alterations were gains of Xp (15 cases, 43%) and Xq (21 cases, 60%). This finding was also confirmed by fluorescent in situ hybridization performed on nuclei extracted from 6 specimens. Other common alterations were 1p-, 2q+, 2q-, 4q-, and 4q+. We found no difference between different histologic subtypes, a finding that may be in agreement with the hypothesis of a common clonal origin for the different components. An hitherto-unreported high frequency of X chromosome gains may support the assumption that X-linked genes are involved in the development of this neoplasm.     

A case of 47,XY,+der(15),t(3;15) (p25;qll)pat presenting as partial 3p trisomy syndrome with multiple joint contractures

Partial 3p trisomy is a rare chromosomal syndrome which results in a characteristic phenotype. We present a case of partial 3;15 trisomy with clinical features of partial 3p trisomy syndrome and multiple joint contractures.     

Prenatal Diagnosis of an Inherited Translocation Between Chromosomes No. 9 and 18

A phenotypically normal woman has an apparently balanced reciprocal translocation between chromosomes No. 9 and No. 18 (translocation 9p-; 18p+), which was transmitted in an unbalanced state to an infant and a fetus. In the latter instance, chromosome analysis of cultured amniotic cells disclosed an abnormal karyotype, which was identical to that of the first affected child. The therapeutically aborted fetus was grossly abnormal and resembled the affected child. The physical features noted are those frequently associated with chromosome abnormalities, although not diagnostic for any specific syndrome. We presume that the chromosome abnormality in the affected offspring represents partial duplication of the short arm of chromosome No. 9 and partial deletion of the short arm of chromosome No. 18. No marked resemblance is noted between these cases and reported cases of trisomy 9 or of partial deletion of the short arm of 18.     

Auto-immune disorders in a child with PIK3CD variant and 22q13 deletion

22q13 deletion syndrome is a genetic disorder caused by the deletion or disruption of the segment of the long arm of chromosome 22. The characteristic clinical features of this syndrome include delayed expressive speech, autistic behavior and hypotonia, and clinically severe complications associated with autoimmunity are rarely reported. We herein report a girl with 22q13 deletion syndrome complicated with multiple inflammatory and autoimmune diseases during early childhood. We performed whole-exome sequencing to identify the genes responsible for her autoimmune diseases and identified the de novo variant p.R512W in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) gene. We suspected it to be the disease-causing variant at the conserved residue in PIK(3)C p110δ. Alternatively, haplo-insufficiency of SHANK3 or other genes by 22q13 deletion and the PIK3CD variant might have synergistically contributed to the onset of the distinctive clinical manifestations in this patient.