Proximal Short Arm Of Chromosome Research Articles

Aarskog-Scott syndrome: phenotypic and genetic heterogeneity

AbstractAarskog-Scott syndrome (AAS) is a rare developmental disorder which primarily affects males and has a relative prevalence of 1 in 25,000 in the general population. AAS patients usually present with developmental complications including short stature and facial, skeletal and urogenital anomalies. The spectrum of genotype-phenotype correlations in AAS is unclear and mutations of the FGD1 gene on the proximal short arm of chromosome X account for only 20% of the incidence of the disorder. Failure to identify pathogenic variants in patients referred for FGD1 screening suggests heterogeneity underlying pathophysiology of the condition. Furthermore, overlapping features of AAS with several other developmental disorders increase the complexity of diagnosis. Cytoskeletal signaling may be involved in the pathophysiology of AAS. The FGD1 protein family has a role in activation of CDC42 (Cell Division Control protein 42 homolog) which has a core function in remodeling of extracellular matrix and the transcriptional activation of many modulators of development. Therefore, mutations in components in the EGFR1 (Epidermal Growth Factor Receptor 1) signaling pathway, to which CDC42 belongs, may contribute to pathophysiology. Parallel sequencing strategies (so-called next generation sequencing or high throughput sequencing) enables simultaneous production of millions of sequencing reads that enormously facilitate cost-effective identification of cryptic mutations in heterogeneous monogenic disorders. Here we review the source of phenotypic and genetic heterogeneity in the context of AAS and discuss the applicability of next generation sequencing for identification of novel mutations underlying AAS.

Prenatal and postnatal findings in a 10.6 Mb interstitial deletion at 10p11.22-p12.31.

Interstitial deletion of the proximal short arm of chromosome 10 represents a rare genetic alteration. Literature review revealed that only 10 postnatal diagnosed clinical cases with deletions overlapping 10p12p11 were published until present. We report the first prenatal diagnosis and postnatal findings in a male fetus with a 10.6 Mb interstitial deletion of the short arm of chromosome 10 (10p11.22-p12.31).

Interstitial 10p11.23-p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism.

Cryptorchidism is the most common genital problem encountered in males and is associated with many chromosomal disorders; however, the genetic factors are mostly unknown. To delineate critical genes affecting testicular migration, we performed genotype-phenotype correlation in patients with deletions involving the proximal short arm of chromosome 10 (10p11-p12), a rare abnormality characterized by developmental delay, craniofacial abnormalities, and in some cases, cryptorchidism. Here we report on a male patient with developmental delay, mild craniofacial dysmorphism, bilateral cryptorchidism, and an 850-kb deletion, within the 10p11.2 region, involving three genes-MKX, ARMC4, and MPP7-as determined by array comparative genomic hybridization analysis. Comparison with four previously reported male patients with overlapping deletions revealed a 140-kb common region, containing the MKX gene, in association with cryptorchidism. The MKX gene is a member of the three amino acid loop extension (TALE) superclass of homeobox genes that is expressed in developing male gonads (male gonadal ridge and testis cords) in temporal relationship to SOX9, a critical regulator of sexual differentiation. Our results suggest that haploinsufficiency of the MKX gene may affect the developmental process during testis migration or serve as a genetic susceptibility locus for cryptorchidism. We propose that deletions of the proximal 10p represent a contiguous gene syndrome; therefore, patients may present with a complex phenotype, depending on the extent of the deletion.

A 137‐kb deletion within the Potocki–Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia

Potocki-Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes.

Cytogenetics of hepatoblastoma

The cytogenetics of hepatoblastoma demonstrate recurring events which include whole chromosome trisomies, most commonly trisomy of chromosome 2, 8, or 10. In addition, unbalanced translocations involving a breakpoint on the proximal short arm of chromosome 1 are observed which result in a duplication of the long arm of chromosome 1q. The most commonly involved reciprocal chromosomal arm is 4q, although the reciprocal chromosome is highly variable and always results in a loss of chromosomal material. The full significance of these chromosomal changes has yet to be confirmed in large studies, however a suggestion of an association of duplication of regions of 2q with a poor prognosis. A rare sub-type of hepatoblastoma, known as the small cell undifferentiated variant, is associated with deletion or translocation of 22q, the locus of the rhabdoid tumor gene, SMARCB1.

Interstitial Deletions of the Short Arm of Chromosome 4 in a Patient With Mental Retardation and Focal Seizure

Interstitial deletion of the proximal short arm of chromosome 4 has rarely been described. This defect is associated with variable clinical manifestations, including mental retardation, unusual facial appearance, and minor limb abnormalities. We describe a girl diagnosed with moderate mental retardation and seizures with an interstitial deletion of the short arm of chromosome 4 [46, XX, del(4)(p12p15.2)].

Variation in GABA‐A subunit gene copy number in an autistic patient with mosaic 4 p duplication (p12p16)

Autism has been associated with chromosomal aberrations, including duplications at chromosome 4, and the identification of genetic factors contributing to the etiology of this disease is the focus of much research. Here we report a Japanese girl with mosaic of chromosome 4p duplication, mos 46,XX,dup(4)(p12p16)[54]/46,XX[6], who was diagnosed with autism at 3 years of age. Fluorescence in situ hybridization (FISH) with probes covering the region spanning a cluster of the gamma aminobutyric acid A (GABA-A) receptor subunit genes in the proximal short arm of chromosome 4 demonstrated total three signals for the GABRG1, GABRA4, and GABRA2 genes, but only two signals for GABRB1. This suggests that aberrant copy number of the GABA-A receptor subunit genes may contribute to the etiology of autism in this patient.

Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature

The proximal chromosome 11p contiguous gene deletion syndrome (P11pDS), also known as Potocki-Shaffer syndrome (PSS) or DEFECT 11 (OMIM 601224), is a disorder associated with foramina parietalia permagna and multiple osteochondroma (exostoses). Additional features include mental retardation, craniofacial anomalies, seizures and genitourinary abnormalities. Here, clinico-pathological findings of a unique patient with all of these features and, additionally, enlarged ventricles, hypertrophic obstructive cardiomyopathy and adipositas are described. The brain showed malformative lesions with hallmarks of disturbed bulk growth including micrencephaly, periventricular nodular heterotopias and focal cortical dysplasia in the nodulus of the cerebellar vermis. In addition, symmetric foci with vacuolation of the underlying neuropil, intermingled macrophages and large bizarre, partially vacuolated, reactive astrocytes were found. The proximal short arm of chromosome 11 harbors several candidate genes that could explain the patient's signs and symptoms including ALX4 and EXT2, which are always present in the interstitial deletion of the short arm of chromosome 11 in PSS. In addition, MYBPC3 would be a good candidate for the hypertrophic cardiomyopathy. Furthermore, adipositas might be related to the MAPK8IP1 gene. To the best of our knowledge, the present patient is the oldest one so far described with PSS phenotype and the only case that has undergone detailed neuropathological investigation.

Interstitial deletion of a proximal 3p: A clinically recognisable syndrome

Interstitial deletions of the proximal short arm of chromosome 3 occurring as constitutional aberrations are rare and a defined clinical phenotype is not established yet. We report on a 30-months-old girl with distinct facial features (square facies, plagiocephaly, broad forehead, broad nasal bridge, long philtrum and low set ears) and psychomotor/speech delay associated with an interstitial deletion of 3p12 chromosomal band, del(3)(p12p12). Clinical manifestations of our child were compared with those of other eight patients with the same deletion previously described to further delineate the proximal 3p deletion syndrome.

Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

Rearrangements of our genome can be responsible for inherited as well as sporadic traits. The analyses of chromosome breakpoints in the proximal short arm of Chromosome 17 (17p) reveal nonallelic homologous recombination (NAHR) as a major mechanism for recurrent rearrangements whereas nonhomologous end-joining (NHEJ) can be responsible for many of the nonrecurrent rearrangements. Genome architectural features consisting of low-copy repeats (LCRs), or segmental duplications, can stimulate and mediate NAHR, and there are hotspots for the crossovers within the LCRs. Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes. Genomic rearrangements may cause Mendelian diseases, produce complex traits such as behaviors, or represent benign polymorphic changes. The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, gene interruption, generation of a fusion gene, position effects, unmasking of recessive coding region mutations (single nucleotide polymorphisms, SNPs, in coding DNA) or other functional SNPs, and perhaps by effects on transvection.

Trisomy 17p10‐p12 due to mosaic supernumerary marker chromosome: Delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications

The unstable, gene-rich chromosome region 17p11.2-p12 is associated with various structural aberrations including supernumerary marker chromosomes (SMCs). In some cases, SMC(17)s utilize the same substrates for recombination as the common recurrent 17p11.2 and 17p12 rearrangements. We report on a 9-year-old girl with a de novo mosaic SMC(17). The der(17) encompasses genetic material from 17p10-p11.2 and is present in 97% of peripheral blood lymphocytes and in 79% of buccal cells. The patient has few features similar to individuals with duplication 17p11.2 including mental retardation, language impairment, and sleep disturbances but has normal growth, and no structural abnormalities of the heart, kidneys, or brain. She has no substantial behavioral abnormalities or dysmorphic features. Molecular analyses determined that the der(17) contains RAI1 but not PMP22. We found one chromosome breakpoint within the centromere and the second breakpoint within the distal Smith-Magenis syndrome low-copy repeat (distal SMS-REP). Recently we characterized the breakpoints of three other marker chromosomes originating from the proximal short arm of chromosome 17. In all four cases, one breakpoint maps within the centromere and in three cases the second breakpoint maps within a low-copy repeat. We thus propose that genome architecture may play a significant role in the formation of marker chromosomes. We present the cytogenetic, molecular, and clinical data of this patient and compare our results with those of patients with dup(17)(p11.2p11.2) syndrome and other patients with SMC(17).

Familial interstitial deletion of chromosome 4 (p15.2p16.1)

Interstitial deletion of the proximal short arm of chromosome 4, extending from p14 to p16.1 region, results in a distinct clinical syndrome. This proximal 4p deletion syndrome is characterized by variable degrees of mental retardation, unusual facies and minor dysmorphic features. Majority of the patients also show a tall, ectomorphic habitus and normal to excessive linear growth with age. While there have been several cases of such interstitial del(4p) cases reported, familial transmission of this condition has not been documented in the literature. This is the first report of a familial transmission of proximal del(4p) from a mother to her daughter, with both patients showing similar features. This report of the familial transmission of del(4p) has wider implications in genetic counseling.

The sex determination in Ellobius lutescens remains bizarre

Mammalian sex determination and gonad differentiation are the result of a complex interaction of fine-tuned spatial and temporal gene expression with threshold levels of individual genes. The male pathway is initiated by SRY. Some exceptional mammals determine male sex without the SRY gene and even without a Y chromosome. Ellobius lutescens in this report is one example of this “weird” species. We provide key data on the genomic level that there are no coarse differences in the genomes of male and female animals by comparative genomic hybridization. On the gene level we studied the gene Nr5a1 for the orphan nuclear receptor, steroidogenic factor SF-1, a central constituent for gonad differentiation and adrenal gland development. The Ellobius lutescens Nr5a1 gene was mapped to the proximal short arm of chromosome 2 by fluorescence in situ hybridization. In addition, we provide evidence by linkage analysis in two E. lutescens pedigrees that Nr5a1 is not the key male sex-determining gene in Ellobius lutescens.

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

Deletion (9) (p13.1 p21.1)

We report on a 22-month-old girl with minor facial anomalies, global developmental delay, growth retardation, seizures, and leukoencephalopathy. Initial clinical assessment suggested the diagnosis of Williams syndrome. Results of fluorescence in situ hybridization testing for elastin were normal. However, chromosome analysis showed a 46,XX,del(9)(p13.1p21.1) karyotype in peripheral lymphocytes. Parental chromosomes were normal, indicating a de novo deletion. This patient's manifestations are compared with those of two other cases with overlapping deletions of the proximal short arm of chromosome 9.

DNA Rearrangements on Both Homologues of Chromosome 17 in a Mildly Delayed Individual with a Family History of Autosomal Dominant Carpal Tunnel Syndrome

Disorders known to be caused by molecular and cytogenetic abnormalities of the proximal short arm of chromosome 17 include Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Smith-Magenis syndrome (SMS), and mental retardation and congenital anomalies associated with partial duplication of 17p. We identified a patient with multifocal mononeuropathies and mild distal neuropathy, growth hormone deficiency, and mild mental retardation who was found to have a duplication of the SMS region of 17p11.2 and a deletion of the peripheral myelin protein 22 (PMP22) gene within 17p12 on the homologous chromosome. Further molecular analyses reveal that the dup(17)(p11.2p11.2) is a de novo event but that the PMP22 deletion is familial. The family members with deletions of PMP22 have abnormalities indicative of carpal tunnel syndrome, documented by electrophysiological studies prior to molecular analysis. The chromosomal duplication was shown by interphase FISH analysis to be a tandem duplication. These data indicate that familial entrapment neuropathies, such as carpal tunnel syndrome and focal ulnar neuropathy syndrome, can occur because of deletions of the PMP22 gene. The co-occurrence of the 17p11.2 duplication and the PMP22 deletion in this patient likely reflects the relatively high frequency at which these abnormalities arise and the underlying molecular characteristics of the genome in this region.

Unusual EEG pattern linked to chromosome 3p in a family with idiopathic generalized epilepsy.

To map the gene causing an unusual EEG pattern of delta bursts that appears to segregate as an autosomal dominant trait in an Italian family. The EEG pattern was observed in four family members affected by idiopathic generalized epilepsy (IGE) and in six other clinically unaffected members. All available family members underwent clinical and EEG examination. DNA samples were obtained and used to perform a whole-genome scan with 270 microsatellite markers. After the first linked marker was identified, 12 additional markers in the same chromosomal region were tested to confirm linkage and define a candidate interval. The gene responsible for the EEG trait was mapped to an 11-cM interval on the proximal short arm of chromosome 3 (3p14.2-p12.1). In this family, a characteristic EEG activity is due to the effect of a single gene on chromosome 3p. A gene encoding a Ca2+ channel subunit maps in the interval and is a potential candidate for the trait. The clinical expression of epilepsy in four family members may reflect the interaction of additional genes, though environmental or other factors cannot be excluded.

Homozygosity Mapping of Autosomal Recessive Retinitis Pigmentosa Locus (RP22) on Chromosome 16p12.1–p12.3

Autosomal recessive retinitis pigmentosa (arRP) is a genetically and clinically heterogeneous and progressive degenerative disorder of the retina, leading usually to severe visual handicap in adulthood. To date, disease loci/genes have been mapped/identified only in a minority of cases. DNA samples were collected from 20 large consanguineous Indian families, in which arRP segregated and that were suitable for homozygosity mapping of the disease locus. After excluding linkage to all known arRP loci, a genome-wide scan was initiated. In two families, homozygosity mapping, haplotype analysis, and linkage data mapped the disease locus (RP22) in an approximately 16-cM region between D16S287 and D16S420 on the proximal short arm of chromosome 16. No mutation has been found by direct sequencing in the gene (CRYM) encoding μ crystallin, which maps in the critical region.

Mapping of a Putative Tumor Suppressor Locus to Proximal 7p in Wilms Tumors

Different findings suggest that alterations of chromosome 7 genes play a role in the development of Wilms tumors. To define the positions of these genes, we have accomplished a combined cytogenetic and molecular study on 11 sporadic Wilms tumors. In one case, where both chromosomes 7 were rearranged, the karyotypic picture was consistent with the presence of a tumor suppressor gene at 7p15. To test this hypothesis, a loss of heterozygosity analysis was performed using microsatellite markers. This revealed a common region of allele losses mapped to the proximal short arm of chromosome 7 and defined the position of the gene(s) involved in Wilms tumors within an interval of approximately 25 cM.

Nested polymerase chain reaction study of 53 cases with Turner's syndrome: is cytogenetically undetected Y mosaicism common?

Turner's syndrome patients with Y mosaicism face a high risk of developing gonadoblastoma. Cytogenetic analysis can fail to detect rare cells bearing a normal or structurally abnormal Y chromosome (low level Y mosaicism). We screened 53 individuals with Turner's syndrome for presence of sex-determining region Y (SRY), the testis-specific protein, Y encoded, gene, and the Y centromeric DYZ3 repeat using nested polymerase chain reaction (PCR). Thirty girls (57%) had the 45,X karyotype, determined through standard analysis of blood lymphocytes. The remaining 23 girls (43%) were mosaics and/or had structural abnormalities in 1 X-chromosome. Genomic DNA from blood leukocytes was amplified using 2 rounds of PCR. This method was sensitive enough to detect 0.0001% male DNA on a female background. None of 53 Turner's syndrome cases was positive for Y-specific loci after the first round of PCR. After the second round, 2 of 53 Turner's syndrome cases were positive for SRY mapping to the distal short arm of chromosome Y. In 1 SRY-positive subject, the karyotype was 45,X, and in the other, it was 46,Xi(Xq). None of 53 Turner's syndrome individuals, including the 2 SRY-positive subjects, were positive for the testis-specific protein, Y encoded, gene on the proximal short arm of chromosome Y or the centromeric DYZ3 repeat. These data exclude low level Y mosaicism in almost all Turner's syndrome cases tested.