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Funduscopic photographs showing defective fundus pigmentation with macular hypoplasia in both eyes. (A) Right, (B) Left eye.
Source publication
Terminal or interstitial deletions of Xp (Xp22.2→Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KA...
Citations
... Several genetic studies of Korean patients with XLI attributed to STS mutations have been documented [4][5][6][7]. In this report, we describe the identification of STS and PUDP deletions using targeted panel sequencing combined with copy-number variation (CNV) analysis in XLI. ...
X-linked recessive ichthyosis (XLI) is clinically characterized by dark brown, widespread dryness with polygonal scales. We describe the identification of STS and PUDP deletions using targeted panel sequencing combined with copy-number variation (CNV) analysis in XLI. A 9-month-old infant was admitted for genetic counseling. Since the second day after birth, the infant’s skin tended to be dry and polygonal scales had accumulated over the abdomen and upper extremities. The infant’s maternal uncle and brother (who had also exhibited similar skin symptoms from birth) presented with polygonal scales on their trunks. CNV analysis revealed a hemizygous deletion spanning 719.3 Kb on chromosome Xp22 (chrX:7,108,996–7,828,312), which included a segment of the STS gene and exhibited a Z ratio of −2 in the proband. Multiplex ligation-dependent probe amplification (MLPA) confirmed this interstitial Xp22.31 deletion. Our report underscores the importance of implementing CNV screening techniques, including sequencing data analysis and gene dosage assays such as MLPA, to detect substantial deletions that encompass the STS gene region of Xq22 in individuals suspected of having XLI.
... respectively) had been reported in (Xp22.33-Xp22.12) without any sign of ovarian dysgenesis [7][8][9]. Therefore, we considered ovarian dysgenesis in our case might have been due to Xq deletion rather than Xp deletion. ...
... Moreover, the loss of different genetic material leads to different clinical phenotypes in Turner syndrome, and the chromosomal karyotype and clinical phenotype are dependent. Short stature is the most common characteristic, and is caused by the perturbations of the SHOX gene on Xp22.3 [7,8,13]. The key region determining the development of female gonads is in Xq21-Xq27, and the disruption of these regions will lead to female ovarian dysplasia [14,15]. ...
Background
Ring chromosomes can be formed by terminal breaks of two arms of a chromosome and their rejoining, leading to a loss of genetic material. They may also be formed by telomere-telomere fusions with no deletion, resulting in the formation of a complete ring. Mosaic X-ring chromosomes are extremely rare and have highly variable phenotypes. Here, we report a case with a mosaic X-ring chromosome in a patient with Turner syndrome, and we illustrate the unreported complicated mechanism using chromosome analysis and fluorescence in situ hybridization ( FISH).
Case presentation
A 10-year-old girl of short stature presenting Turner syndrome was admitted to our hospital. The patient’s clinical characteristics were subsequently documented. Genetic analysis showed a karyotype of mostly 45,X[140]/46,X,r(X)[60]. The X ring chromosome was cytogenetically characterized as 45,X/46,X,r(X)(p22.32q21.1), with a length of approximately 74 Mb.
Conclusions
Taken together, we report a rare case with a mosaic X ring chromosome in Turner syndrome and we believe this case expands our collective knowledge of mosaic structural chromosomal disorders and provides new insight into clinical management and genetic counseling for Turner syndrome.
... The difference is that deletion in the latter region is mosaic; a 52.27 Mb deletion of Xp22.33p11.22(312708_52587526)x1 [18,19] confirmed a single-copy loss of the Xp arm in accordance with the NIPT results ( Figure 1). ...
Prenatal testing has been moving towards non-invasive methods to determine fetal risk for genetic disorders. Numerous studies have focused the attention on common trisomies; although the detection rate (DR) for trisomy 21 is high (over 95%), the accuracy regarding the DR for trisomies 13 and 18 has come under scrutiny. The testing has been applied to sex chromosome aneuploidies, but many studies have shown that it is not as effective as it is for common trisomies. Although non-invasive prenatal test (NIPT) has become a standard screening procedure for all pregnant women, invasive sampling procedures remain important in confirming NIPT-positive findings. In the present study, we report discordant results of Turner syndrome (TS) mosaicism between NIPT and karyotyping. A 35-year-old pregnant woman underwent NIPT, and a probable risk for Xp deletion was indicated. Subsequently, amniocentesis was performed. The karyotype was identified as mos 45,X [28]/46,X,i(X)(q1.0)[5]. In the second case, a 33-year-old woman underwent amniocentesis after a positive NIPT that indicated a probable risk for monosomy X. The result was mos 45,X [8]/46,XY[8]. Since NIPT is a screening test, the possibility of false-positive or false-negative results should always be considered. We underline the importance of pre/post detailed counseling. Furthermore, women with abnormal NIPT results should undergo immediate amniocentesis that remains the only tool for a correct diagnosis of sex chromosome aneuploidies.
... We did a literature review on case reports of KS with XLI, and the genotype-phenotype association of 20 cases was analyzed (Supplementary Table S2). This analysis revealed that 7 of the 20 patients had an intellectual disability (Klink et al., 1994;Martul et al., 1995;Weissörtel et al., 1998;Macarov et al., 2007;Melichar et al., 2007;Cho et al., 2012;Khelifa et al., 2013). Three of these patients had an NLGN4X deletion, while three patients did not (Martul et al., 1995;Weissörtel et al., 1998;Macarov et al., Melichar et al., 2007;Cho et al., 2012;Khelifa et al., 2013), and one case was unclear (Klink et al., 1994). ...
... This analysis revealed that 7 of the 20 patients had an intellectual disability (Klink et al., 1994;Martul et al., 1995;Weissörtel et al., 1998;Macarov et al., 2007;Melichar et al., 2007;Cho et al., 2012;Khelifa et al., 2013). Three of these patients had an NLGN4X deletion, while three patients did not (Martul et al., 1995;Weissörtel et al., 1998;Macarov et al., Melichar et al., 2007;Cho et al., 2012;Khelifa et al., 2013), and one case was unclear (Klink et al., 1994). There were three other cases with an NLGN4X deletion that demonstrated normal mental development (Mochel et al., 2008;Liu et al., 2016;Nagai et al., 2017). ...
... Among 17 patients with either X-linked KS or X-linked KS and XLI, 6 patients had only one kidney (Kirk et al., 1994). Obesity occurred in 5 of the 20 patients (Martul et al., 1995;Weissörtel et al., 1998;Cho et al., 2012;Khelifa et al., 2013;Berges-Raso et al., 2017). Among four cases with deletion of PNPLA4, two patients were obese, and one had fatty liver and hyperlipidemia (Cho et al., 2012;Khelifa et al., 2013;Liu et al., 2016;Nagai et al., 2017). ...
Background
A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively.
Method
Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype–phenotype association for each patient were analyzed.
Results
We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838–9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083–8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient.
Conclusion
We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.
... Albinism represents a group of genetic abnormalities caused by a deficiency in animal pigment synthesis, associated with a normal number and structure of melanocytes. The foremost obvious [1,2] of albinism is the physiological condition [3]. And Oculocutaneous albinism type 4 is a newly identified human autosomal enlightened hypopigmentary disorder that disrupts pigmentation in the skin, hair, and eyes [4]. ...
Pigment synthesis, associated with a normal number and structure of melanocytes. Oculocutaneous Albinism (OCA) may be a common phenotype for a bunch of recessive genetic disorders of instinctive pigment synthesis. The two noteworthy classifications of albinism incorporate oculocutaneous albinism characterized by a checked decrease in creature color all through the body and albinism portrayed by hypomelanosis of exclusively the iris and furthermore the retinal epithelial tissue. Vision issues in albinism result from strange improvement of nerve associations between the eye and the cerebrum because of their low or absence of shading/ melanin. As most people with serious types of OCA are inclined to sunburn, the ancestor basal cell of sun-uncovered skin of pale skinned people is at incredible danger of experiencing daylight actuated dangerous transformation. SCCS in pale skinned people can emerge again or from premalignant actinic sores. This genomic instability predisposes the initially transformed keratinocytes to additional genetic alterations and may drive the processes of clonal divergence with consequent clonal expansion of keratinocytes possessing a selective growth advantage, ultimately giving rise to a frank SCCS. Daylight consistently causes these hereditary changes that are alluded to as UVR-related "signature transformations" and these mark transformations drive the threatening change of daylight incited SCCS. At first changed keratinocytes are immunogenic anthus produce safe reactions which can tweak or control signature transformations however daylight instigated immunosuppression may basically meddle with this defensive mechanism.
... But it is difficult to ascertain the impact of mosaicism on clinical phenotype as level of mosaicism has been reported to go down with age due to unstable nature of r (X) chromosomes [2]. Further, we compared Xp deletions and clinical manifestation observed in our cases with previously reported cases where there is no evidence for ovarian dysgenesis with an Xp terminal deletion [4,13,26,28,47,49]. Fertility has been reported to be maintained even when more than two third of the Xp is deleted [16]. ...
... and Xpter-Xp22.31, respectively) had been reported in [4,49] (Xp22.33-Xp22.12) without any sign of ovarian dysgenesis. ...
Purpose
In the present study, we reported two cases of TS with mosaic ring X chromosome showing common clinical characteristics of TS like growth retardation and ovarian dysfunction. The purpose of the present study was to cytogenetically characterize both cases.
Methods
Whole blood culture and G-banding were performed for karyotyping the cases following standard protocol. Origin of the ring chromosome and degree of mosaicism were further determined by fluorescence in situ hybridization (FISH). Breakpoints and loss of genetic material in formation of different ring X chromosomes r (X) in cases were determined with the help of cytogenetic microarray.
Results
Cases 1 and 2 with ring chromosome were cytogenetically characterized as 45, X [114]/46Xr (X) (p22.11q21.32) [116] and 45, X [170]/46, Xr (X) (p22.2q21.33) [92], respectively. Sizes of these ring X chromosomes were found to be ~75 and ~95 Mb in cases 1 and 2, respectively, using visual estimation as part of cytogenetic observation. In both cases, we observed breakpoints on Xq chromosome were within relatively narrow region between Xq21.33 and Xq22.1 compared to regions in previously reported cases associated with ovarian dysgenesis.
Conclusions
Our observation agrees with the fact that despite of large heterogeneity, severity of the cases with intact X-inactive specific transcript (XIST) is dependent on degree of mosaicism and extent of Xq deletion having crucial genes involved directly or indirectly in various physiological involving ovarian cyclicity.
Context
The genetic architecture of Isolated Hypogonadotropic Hypogonadism (IHH) has not been completely defined.
Objective
To determine the role of copy number variants (CNVs) in IHH pathogenicity and define their phenotypic spectrum.
Design
Exome sequencing (ES) data in IHH probands and family members was analyzed for CNVs and single nucleotide variants (SNVs)/indels in 62 known IHH genes. IHH subjects without SNVs/indels in known genes were considered “unsolved”. Phenotypes associated with CNVs were evaluated through review of patient medical records.
Setting
The Reproductive Endocrine Unit and the Center for Genomic Medicine of Massachusetts General Hospital.
Patients or other participants
IHH probands [n=1,394: Kallmann Syndrome (KS): IHH with anosmia (n=706); normosmic IHH (nIHH) (n=688] and their family members (n= 1092).
Interventions/Main Outcome Results
A total of 29 CNVs in 13 genes were detected (overall IHH cohort prevalence: ~2%). Almost all (28/29) CNVs occurred in unsolved IHH cases. While some genes (e.g., ANOS1 and FGFR1) frequently harbor both CNVs and SNVs/indels, the mutational spectrum of others (e.g., CHD7) was restricted to SNVs/indels. Syndromic phenotypes were seen in 83% and 63% of IHH subjects with multigenic and single gene CNVs, respectively.
Conclusions
CNVs in known genes contribute to ~2% of IHH pathogenesis. Predictably, multigenic contiguous CNVs resulted in syndromic phenotypes. Syndromic phenotypes resulting from single gene CNVs validate pleiotropy of some IHH genes. Genome sequencing approaches are now needed to identify novel genes and/or other elusive variants (e.g., non-coding/complex structural variants) that may explain the remaining missing etiology of IHH.
Background:
Xp22.3 region is characterized by low frequency of interspersed repeats and low GC content. Several clinically important genes including ANOS1 (KAL1) reside in this region. This gene was first identified due to translocation between chromosomes X and Y in a patient with Kallmann syndrome.
Case presentation:
A 20 year old male presented with complaints of delayed secondary sexual characteristics, impaired sense of smell, and poor scholastic performance. On examination, he had short stature (151 cm; <3rd centile). His sexual maturity corresponded to Tanner stage 3. Stretched penile length was 3.6 cm (<3rd centile). Right testis was undescended with low left testicular volume (12 ml). There was mild ichthyosis over abdomen and back. He had hyposmia, hoarse voice, and synkinesia. Investigations were suggestive of hypogonadotrophic hypogonadism. Karyotype revealed an extra chromosomal material on p arm of chromosome X (46,Xp+,Y). On cytogenetic microarray, deletion of 8.3 Mb on Xp22.33 region and duplication of 12.8 Mb on Yq11.22 region were identified. The breakpoint on X chromosome resulted in deletion of exons 7-14 of ANOS1 gene and complete STS, NLGN4X, ARSL (ARSE), SHOX, and VCX genes.
Conclusion:
Patients diagnosed with Kallmann syndrome should receive careful clinical evaluation to detect presence of a contiguous gene syndrome.
Recessive X‐linked ichthyosis (XLI), the second most common ichthyosis, is caused by mutations in the STS gene encoding the steroid sulfatase enzyme. A complete deletion of the STS gene is found in 85‐90% of cases. Rarely, larger deletions involving contiguous genes are detected in syndromic patients. We report the clinical and molecular genetic findings in a series of 35 consecutive Italian male patients. All patients underwent molecular testing by MLPA or aCGH, followed, in case of negative results, by next generation sequencing analysis. Neuropsychiatric, ophthalmological and pediatric evaluations were also performed. Our survey showed a frequent presence of disease manifestations at birth (42.8%). Fold and palmoplantar surfaces were involved in 18 (51%) and 7 (20%) patients, respectively. Fourteen patients (42%) presented neuropsychiatric symptoms, including attention deficit hyperactivity disorder and motor disabilities. In addition, two patients with mental retardation were shown to be affected by a contiguous gene syndrome. Twenty‐seven patients had a complete STS deletion, one a partial deletion and 7 carried missense mutations, two of which previously unreported. In addition, a de novo STS deletion was identified in a sporadic case. The frequent presence of palmoplantar and fold involvement in XLI should be taken into account when considering the differential diagnosis with ichthyosis vulgaris. Our findings also underline the relevance of involving the neuropsychiatrist in the multidisciplinary management of XLI. Finally, we report for the first time a de novo mutation which shows that STS deletion can also occur in oogenesis.
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