Analysis of RS1 gene variant in a Chinese pedigree affected with X-linked congenital retinal splitters / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with X-linked retinoschisis.@*METHODS@#Clinical data of the pedigree was collected. Following DNA extraction, PCR and Sanger sequencing were carried out to detect potential variant in the RS1 gene. The result was verified by using PCR and restriction fragment length polymorphism assay.@*RESULTS@#All male patients were found to harbor a c.458T>G (p.Val153Gly) variant of the RS1 gene, for which Their mothers were heterozygous carriers. The same variant was not detected among unaffected members of the pedigree as well as 100 healthy controls. Bioinformatic analysis suggested the variant to be pathogenic.@*CONCLUSION@#The c.458T>G (p.Val153Gly) variant of the RS1 gene probably underlay the X-linked retinoschisis in this pedigree.

Mutación de protocadherina 19 (PC-DH19), en paciente con epilepsia refractaria / Mutation of protocadherin 19 (PCDH19), in patients with refractory epilepsy

Paciente de 4 años de edad, con epilepsia de difícil manejo, cuya etiología se atribuye a patología autoinmune y que finalmente se diagnostica una mutación de protocadherina (PCDH19). Se discute la fisiopatología, características clínicas, exámenes y los posibles tratamientos.

Four-year-old patient with intractable epilepsy, whose etiology is attributed to autoimmune pathology and who is eventually diagnosed with a protocadherin mutation (PCDH19). Pathophysiology, clinical characteristics, examinations and possible treatments are discussed.

Clinical and mutational analysis of 7 children with X-linked adrenal dysplasia congenita / 中华医学遗传学杂志

OBJECTIVE@#To summarize clinical manifestations, inheritance pattern and mutations of NR0B1 gene in 7 children with X-linked adrenal dysplasia congenita (XL-AHC).@*METHODS@#Clinical data of the 7 children was collected. Next-generation sequencing was carried out to detect potential mutations in the coding regions of adrenal gland-related genes. Suspected mutations were verified with Sanger sequencing.@*RESULTS@#In all of the children, the initial symptom was adrenocortical insufficiency. Five cases had neonatal onset, while the remaining two developed it at the age of 2. Three cases (42.9%) had a short stature and 1 showed growth retardation (14.3%). Of the 7 cases, 6 (85.7%) had mutations occurring in exon 1, and 1 (14.3%) had it occurring in exon 2. Four cases (57.1%) were frameshift mutations, 2 cases (28.6%) were nonsense mutations and 1 case (14.3%) was missense mutation. Two mutations were known to be pathogenic, and 5 had not been reported previously. Maternal inheritance was found in 6 cases. Three children had a maternal uncle died of unexplained causes. The mothers of 2 children had a history of spontaneous abortions. One child had a brother died of unexplained reason.@*CONCLUSION@#Male children with primary adrenal insufficiency should be routinely checked for NR0B1 mutations, especially those with a family history. mutations of NR0B1 gene occur mostly in exon 1, with frameshift mutations being the most common type. The development of all patients with XL-AHC should be closely monitored during follow-up.

A novel mutation in XLRS1 gene in X-linked juvenile retinoschisis

X-linked juvenile retinoschisis (XLRS) is characterized by the progressive loss of visual acuity and vitreous hemorrhage. XLRS is caused by a mutation of retinoschisin 1 (RS1) gene at Xp22.13. In the current report, a 2-year-old Korean patient with XLRS was described. The germline deletion of exon 1 was identified in the RS1 gene. Considering X-linked inheritance pattern, validation of a carrier state of a patient's mother is important for the genetic counseling of other family members and for the future reproductive plan. To confirm the carrier state of his mother, the multiplex ligation-dependent probe amplification analysis was done using peripheral leukocytes and found the heterozygous deletion of exon 1 in his mother.

A family with X-linked Cornelia de Lange syndrome due to a novel SMC1A missense mutation identified by multi-gene panel sequencing

Cornelia de Lange syndrome (CdLS) is a rare, clinically and genetically heterogeneous, multi-system developmental disorder caused by mutations in genes that encode components of the cohesin complex. X-linked CdLS caused by an SMC1A mutation is an extremely rare disease characterized by phenotypes milder than those of classic CdLS. In the Republic of Korea, based on a literature review, one family with SMC1A-related CdLS with mild phenotypes has been genetically confirmed to date. In this study, we describe the clinical features of a Korean boy with a hemizygous novel missense mutation and his mother with a heterozygous mutation, i.e., c.2447G>A (p.Arg816His) in SMC1A, identified by multi-gene panel sequencing. The proband had a mild phenotype with typical facial features and his mother exhibited a mild, subclinical phenotype. This study expands the clinical spectrum of patients with X-linked CdLS caused by SMC1A variants. Moreover, these findings reinforce the notion that a dominant negative effect in a carrier female with a heterozygous mutation in SMC1A results in a phenotype milder than that in a male patient with the same mutation.

Androgen insensitivity syndrome (AIS) / Philippine Journal of Obstetrics and Gynecology

Androgen Insensitivity Syndrome (AIS) is a rare condition, it is an X-linked-mutation that is considered as a disease caused by resistance of androgen receptor to its actions. It is expressed in a variety of phenotypes ranging from male infertility to completely normal female external genitalia. This is a case of a 25 year-old with Complete Androgen Insensitivity Syndrome (CAIS), presented as phenotypical female with secondary sexual development, bilateral inguinal masses. Gonadectomy, estrogen replacement therapy and psychological support are part of long term management.

Progress in molecular genetic studies of retinitis pigmentosa / 中华医学遗传学杂志

Retinitis pigmentosa (RP) is a group of inherited disorders which involve photoreceptors of the retina and can lead to visual loss. The genetic and clinical phenotypes of RP feature high heterogeneity. RP can be divided into nonsyndromic and syndromic types, both may feature autosomal dominant, autosomal reccesive and X-linked inheritance. So far, many genes have been identified, most of which are expressed in the photoreceptors or retinal pigment epithelium. Sixty-three genes have been identified in nonsyndromic RP. This paper reviews recent progress in the research of the genetics of RP.

Clinical and genetic analysis of a Chinese family affected with X-linked Charcot-Marie-Tooth disease / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the clinical manifestations and identify causative mutations for a Chinese family affected with X-linked Charcot-Marie-Tooth disease.</p><p><b>METHODS</b>Clinical, electrophysiological and pathological features of the family were carefully analyzed by neurologists. Blood samples were obtained from the proband and other family members. Genomic DNA was extracted. Mutation analysis of GJB1 gene was analyzed with PCR and direct sequencing.</p><p><b>RESULTS</b>The family has fit with X-linked inheritance, and the affected individuals have typical clinical manifestations. A c.614A>G (p.Asn205Ser) mutation was detected in the GJB1 gene in all affected individuals in the family.</p><p><b>CONCLUSION</b>A c.614A>G (p.Asn205Ser) mutation of GJB1 gene is co-segregated with the disease phenotype in this family and probably underlies the disease.</p>

Identification of Xq22.1-23 as a region linked with hereditary recurrent spontaneous abortion in a family

Recurrent spontaneous abortion [RSA] is one of the most common health complications with a strong genetic component. Several genetic disorders were identified as etiological factors of hereditary X linked RSA. However, more genetic factors remain to be identified. In this study we performed linkage analysis on a large X linked RSA pedigree to find a novel susceptibility locus for RSA. A linkage scan using 11 microsatellites was performed in 27 members of a large pedigree of hereditary X-linked RSA. Two point parametric Linkage was performed using Superlink v 1.6 program. Evidence of linkage was observed to markers at Xq23, DXS7133 and at Xq22.1 DXS101, with LOD score of 3.12 and 1.60, respectively. Identified locus in this study may carry a responsible gene in RSA. Narrowing down of this region may leads to identification of this gene

Determination of hematopoietic clonality by detection of multiple X-linked gene exonic polymorphic loci using transcription-based clonality assays / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the frequencies of heterozygosity in X-linked G6PD, P55, BTK, and FHL-1 gene exonic polymorphic loci among Chinese females and the value of determination of hematopoietic clonality by detection of these X-chromosome exonic polymorphisms based on X-chromosome inactivation patterns (XCIP)-transcription-based clonality assays (TCA).</p><p><b>METHODS</b>Genomic DNA was extracted from peripheral blood of 446 Chinese healthy females. Allele-specific PCR (ASPCR) or PCR-restriction enzyme digestion method was applied for detecting G6PD, P55, BTK and FHL-1 polymorphisms. Those heterozygotic loci were used as markers to examine the hematopoietic clonality of bone marrow mononuclear cells by TCA from essential thrombocythemia (ET) patients with JAK2V617F mutation and myelodysplastic syndrome (MDS) patients with abnormal karyotype.</p><p><b>RESULTS</b>Among the total 446 genomic DNA samples, the frequencies of heterozygosity in G6PD, P55, BTK and FHL-1 loci were 12.8%, 29.4%, 52.0% and 46.4%, respectively. About 81.4% of females were heterozygous at one or more loci. All 10 ET patients with JAK2V617F mutation and 2 MDS patients with abnormal karyotype, which were heterozygotic in either locus, had monoclonal/oligoclonal hematopoiesis.</p><p><b>CONCLUSION</b>Clonality detection based on X chromosome inactivation patterns-transcription based clonality assays is applicable to about 80% of Chinese females.</p>

A Study on the Genetic Inheritance of Ankyloglossia Based on Pedigree Analysis

BACKGROUND: Ankyloglossia or tongue-tie is a congenital anomaly characterized by an abnormally short lingual frenum. Its prevalence in the newborn population is approximately 4%. Its mode of inheritance has been studied in some articles, but no conclusion has been established. Also, no relevant report has been published in Korea. This study was conducted to elucidate the genetic inheritance of ankyloglossia via pedigree analysis. METHODS: In this study, 149 patients with no other congenital anomaly who underwent frenuloplasty between March 2001 and March 2010 were studied. Pedigrees were made via pre- or post-operative history taking, and patients with uncertain histories were excluded. In the patient group that showed a hereditary nature, the male-to-female ratio, inheritance rate, and pattern of inheritance were investigated. RESULTS: One hundred (67.11%) of the patients were male and 49 (32.89%) were female (male-female ratio=2.04:1). Ninety-one (61.07%) patients reported no other relative with ankyloglossia, and 58 (38.93%) patients had a relative with this disease. The inheritance rate was 20.69% in the 58 cases with a hereditary nature. In the group with no family history of ankyloglossia, the male-female ratio was 3.79:1, which significantly differed from that of the group with a family history of ankyloglossia. X-chromosome mediated inheritance and variation in the gene expression was revealed in the pedigree drawn for the groups with hereditary ankyloglossia. CONCLUSIONS: Ankyloglossia has a significant hereditary nature. Our data suggest X-linked inheritance. This study with 149 patients, the first in Korea, showed X-linked inheritance in patients with a sole anomaly.

Mutational screening of ARX gene in Iranian families with X-linked intellectual disability

Mutations in the human aristaless-related homeobox [ARX] gene are amongst the major causes of developmental and neurological disorders. They are responsible for a wide spectrum of phenotypes, including nonsyndromic X-linked intellectual disability [NS-XLID], and syndromic [XLIDS] forms such as X-linked lissencephaly with abnormal genitalia [XLAG], Partington syndrome [PRTS], and X-linked infantile spasm syndrome [ISSX]. The recurrent 24 bp duplication mutation, c.428_451dup[24 bp], is the most frequent ARX mutation, which accounts for 40% of all cases reported to date. We have screened the entire coding sequences of the ARX gene in 65 Iranian families with intellectual disabilities in order to obtain the relative prevalence of ARX mutations. At first these families were screened for the most recurrent mutation, the c.428_451dup[24 bp]. For samples with negative results, single strand conformation polymorphism [SSCP] analysis was performed. We identified one family with the c.428_451dup[24 bp] duplication. Three shifts [one shift in exon 5 and two shifts in exon 4] were also identified among the total families. According to the results of the sequencing analysis, two shifts were not associated with any mutation and the other one was a c.1347C>T [p.G449G] substitution in exon 4. Hence, we suggest that molecular analysis of ARX mutations as a second cause of XLID should be considered as routine diagnostic procedure in any male who presents with either NS-XLID or XLIDS

Haemophilia B: clinical manifestations and complications

Haemophilia B is X-linked recessive inherited disorder of factor IX deficiency. It is classified as severe, moderate and mild depending upon plasma levels of factor IX. The development of inhibitors is seen during treatment of haemophilia B against F-IX. This study was aimed to determine the frequency of different complications in haemophilia B patients. Total 45 patients of Haemophilia B already enrolled in the Haemophilia society of Pakistan Lahore chapter were included in this study. Clinical history and physical examinations were recorded on a pre designed proforma. Laboratory testing for establishment of diagnosis of haemophilia B and inhibitors of FIX was done. Out of 45 patients, 10 [22.2%] had severe disease while 28 [62.2%] had moderate and 07 [15.6%] had mild disease. Twenty nine [64.4%] of patients with severe and moderate disease were diagnosed below 5 years of age while none with mild disease was diagnosed under 5 years of age. Arthropathy was the most frequently developing complication in patients 10 [100%] of severe Hemophilia B. Post circumcision bleeding was found to be the most common first episode of bleeding in patients of haemophilia B 29 [64.4%]. Inhibitor against F-IX developed in only one patient of severe disease 1 [10%]. Arthropathy is the commonest complication and circumcision is the first bleeding site in most of the haemophiliacs

Association of the X-linked Androgen Receptor Leu57Gln Polymorphism with Monomelic Amyotrophy

Monomelic amyotrophy (MA), also known as Hirayama disease, occurs mainly in young men and manifests as weakness and wasting of the muscles of the distal upper limbs. Here, we sought to identify a genetic basis for MA. Given the predominance of MA in males, we focused on candidate neurological disease genes located on the X chromosome, selecting two X-linked candidate genes, androgen receptor (AR) and ubiquitin-like modifier activating enzyme 1 (UBA1). Screening for genetic variants using patients' genomic DNA revealed three known genetic variants in the coding region of the AR gene: one nonsynonymous single-nucleotide polymorphism (SNP; rs78686797) encoding Leu57Gln, and two variants of polymorphic trinucleotide repeat segments that encode polyglutamine (CAG repeat; rs5902610) and polyglycine (GGC repeat; rs3138869) tracts. Notably, the Leu57Gln polymorphism was found in two patients with MA from 24 MA patients, whereas no variants were found in 142 healthy male controls. However, the numbers of CAG and GGC repeats in the AR gene were within the normal range. These data suggest that the Leu57Gln polymorphism encoded by the X-linked AR gene may contribute to the development of MA.

Comparison of serum creatine kinase estimation with short tandem repeats based linkage analysis in carriers and affected children of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy [DMD] is an X-linked recessive lethal, genetic disorder characterised by progressive weakness of skeletal muscles which is untreatable and transmitted to males by carrier females. Advances in laboratory techniques now focus direct mutational analysis as the most reliable and indirect analysis based on Short Tandem Repeats [STR] based linkage analysis as feasible, inexpensive, and efficient method for carrier detection and prenatal diagnosis. The objective of this study was to compare the sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV] and diagnostic efficiency of Serum Creatine Kinase [SCK] with Short Tandem Repeats [STR] based linkage analysis in carriers and affected children of Duchenne Muscular Dystrophy. The study was carried out from Dec 2006 to Dec 2007 in families having index clinical cases of DMD who were referred from different hospitals for evaluation/workup of DMD. SCK was done as a preliminary investigation in all index cases. The PCR assay with STR based linkage analysis with Intron 44, 45, 49 and 50 of DMD gene were performed in all families. Six families were informative with Intron 44 of DMD gene and one family was non-informative with all four intronic markers of DMD. SCK analyses were done in all the family members and compared with PCR analysis in informative families. SCK was not performed on Chorionic villous sample [CVS] done for prenatal diagnosis of DMD, and CVS and non-informative family members were excluded from the study. In carriers of DMD, the sensitivity and negative predictive value of SCK were 33.3%, and specificity and positive predictive were 100% with diagnostic efficiency of 50%. In affected cases of DMD the sensitivity and negative predictive value of SCK were 100%, and specificity and positive predictive were 91% and 88.8% respectively and diagnostic efficiency of 94.1%. The SCK is an excellent screening test for affected cases of DMD. For carrier identification we have to resort on PCR analysis so as to provide safer diagnostic tool for genetic counselling and prenatal diagnosis

A novel missense mutation of FOXP3 causes immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in a Chinese child / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate variation of FOXP3 and it's expression in male children presented with severe and early-onset enteropathy, rash with or without insulin-dependent diabetes mellitus (IDDM).</p><p><b>METHODS</b>Four male children presented with severe and early-onset enteropathy, rash, with or without IDDM were subjected to detection of FOXP3 expression on the PBMC by flow cytometry and FOXP3 gene analysis. The maternal gene analysis was subsequently performed once the variant FOXP3 gene was found. All 11 exons and splice sites within FOXP3 gene were amplified by polymerase chain reaction (PCR) from genomic DNA. Reverse transcription polymerase chain reaction was used to amplify the FOXP3 transcripts. Sequence analysis was performed directly on the bulk PCR products forwardly and reversely. The candidate mutation site was compared with that of 100 healthy controls to exclude polymorphism. Flow cytometry was used to determine FOXP3 expression on CD4+CD25+ T cells and the frequency of Tregs in CD4+ T cells.</p><p><b>RESULTS</b>One of the 4 patients showed a G13128A genetic variation in exon 11, which resulted in a Met370Ile substitution. No sequence variations were found at the same site in any of 100 healthy controls, indicating that the Met370Ile substitution is not a polymorphism but a novel missense mutation. The patient's mother was identified as a carrier for this mutation. There was no reduced frequency of Tregs in the peripheral blood of the patient and FOXP3 protein expression is normal as compared with controls.</p><p><b>CONCLUSION</b>A novel missense mutation of FOXP3 which causes IPEX phenotype was identified in a Chinese child according to immunologic screening and gene sequencing. Infants with early-onset IDDM and persistent diarrhea should be suspected as IPEX, FOXP3 gene analysis will be a reliable diagnostic approach to IPEX.</p>

[Incontinentia pigmenti: report of a case]

The rare case of Incontinentia Pigmenti [IP] also known as Bloch-Sulzberger Syndrome was first introduced by Garrod [1906]. This genetically condition involves the skin followed by the teeth. It is also known as a sex linked dominant trait. Brownish gray spots are routinely seen on abdominal and limber skin. The aim of this report is to illustrate the clinical feature of IP cases with reference to earlier reports. An 8.5 year old girl was referred to the pedodontic department for her lack of teeth. Several missing teeth were noted in both jaws with only a number of teeth being present in mouth with change in form. Patient chief complaint was malfunction in mastication and esthetics. Present teeth in clinical exam were as follows: 51,52,61,62,72,73,83. Patient was available for a follow up appointment after 1.5 year. Both upper permanent central incisors were semi erupted at this stage along with newly erupted upper primary canines. Clinical consultation was obtained from departments of oral pathology, oral pediatrician medicine and medical genetics. The condition was agreed as Bloch-Selzberger Syndrome also named as Incontinentia Pigmenti. Based on the collected clinical evidences including the lack of several teeth Incontinentia Pigmenti was diagnosed in association to hyper pigmented spots on skin of abdominal sides. Preventive and intermediate dental treatments are encouraged in such cases

Lowe syndrome: report of a case and brief literature review

The oculocerebrorenal syndrome of Lowe [OCRL] is a rare x-linked recessive disorder first described in 1952. This syndrome is characterized by ocular involvement, mental retardation and kidney disease. The causative gene is OCRL1. Survival rarely exceeds 40 years. A 13-year-old boy was referred because of short stature. In physical examination his height was 108.2 cm. He had poor growth, psychomotor retardation, severe hypotonia, congenital cataract which was operated on earlier in life, searching nystagmus, anti social behavior and used foul language. He had been on treatment for renal tubular acidosis [Fanconi syndrome] since 8 month of age. The possibility of OCRL should be considered in boys with cataracts and glumerolar disease. As the condition can be diagnosed in first months of life, early treatment can prevent patients from various complications

Identification of a missense mutation in SEDL gene from a Chinese family with X-linked spondyloepiphyseal dysplasia tarda / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify the SEDL gene mutation in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda (SEDL) and to establish a genotyping assay for rapid diagnosis of this X-linked recessive disorder.</p><p><b>METHODS</b>Clinical diagnoses were made based on physical examination, radiological examination and pedigree analysis for this family. Four primer pairs flanking the SEDL exons 3-6 including their exon/intron boundaries were designed. A rapid genotyping assay based on denaturing high performance liquid chromatography (DHPLC) was established to screen the point mutations of the SEDL gene. Genomic DNA was extracted by standard methods from 18 members in the three generations of the pedigree and subjected to PCR-denaturing high performance liquid chromatography (PCR-DHPLC) assay followed by direct DNA sequencing.</p><p><b>RESULTS</b>A c.218C>T mutation in exon 4 of the SEDL gene, which resulted in a substitution of serine 218 with leucine, was identified in this family. Among the 18 members, 3 patients, 5 obligate female carriers and 2 unmarried young females were found to have the missense mutation, and other 8 healthy individuals were not detected to carry the mutation, in which genotype-phenotype correlations were well established in each member investigated in this family.</p><p><b>CONCLUSION</b>A c.218C>T missense mutation in the SEDL gene was firstly reported in Chinese population and the results of this study expand the spectrum of SEDL mutations. The PCR-DHPLC assay is a useful tool to rapidly detect the SEDL mutation in clinical and prenatal diagnosis.</p>

Molecular basis of G6PD deficiency: Current status and its perspective

Glucose-6-phosphate dehydrogenase is an essential enzyme to cell growth. Its deficiency of enzyme plays an important role in senescence and death signaling. Also, it is actually the most common clinically important enzyme defect, not only in hematology, but also among all human known diseases. Clinical consequences of enzyme deficiency are: neonatal hyperbilirubinemia, acute hemolytic anemia, and chronic hemolytic anemia. The enzyme gene spans 18 kb on the X chromosome [xq28] and contains 13 exons. Its promoter is embedded in a CpG island that is conserved from mice to humans. The development of a number of PCR-based methods for the detection of known mutations in Glucose- 6-phosphate dehydrogenase has made it possible to detect enzyme deficiency and identify the specific mutation responsible with relative ease. We will discuss the mentioned clinical manifestations of glucose-6-phosphate dehydrogenase deficiency, Genetics, biochemistry and pathophysiology of the enzyme in details using newer published data and present most of the studies in Iranian population