Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability,macrocephaly, and obesity: A series of 17 patients

BRWD3 has been described as a cause of X‐linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth‐intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.     

RP2‐associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review,identifying a genotype–phenotype association

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X‐linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2‐associated retinal disorder (RP2‐RD) from four Japanese families in a nationwide cohort. A systematic review of RP2‐RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10–47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52–2.0)/1.10 (0.52–1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2‐RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.     

Uruguay facio‐cardio‐musculo‐skeletal syndrome: A novel X‐linked recessive disorder

We report on three male patients from a single family with a brachyturricephaly, “pugilistic” facial appearance, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. Three other males in the family, now deceased from cardiac disease, appear to have had the same disorder. The mother of the propositus has milder signs of the syndrome. All affected males are related through the maternal line. These cases represent an apparently previously undescribed X‐linked recessive syndrome. Am. J. Med. Genet. 95:247–265, 2000.     

A novel RBMX‐TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX‐TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12‐year‐old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break‐apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX‐TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come‐together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break‐apart might be below the FISH resolution, resulting in a false negative result.     

Dissemination of metallo‐β‐lactamase in Pseudomonas aeruginosa isolates in Egypt: mutation in blaVIM‐4

This study was designed to investigate the prevalence of metallo‐β‐lactamase (MBL) in Pseudomonas aeruginosa isolates collected from Suez Canal University Hospital in Ismailia, Egypt. Antibiotic susceptibility testing and phenotypic and genotypic screening for MBLs were performed on 147 isolates of P. aeruginosa. MICs were determined by agar dilution method for carbapenem that was ≥2 μg/mL for meropenem. MBL genes were detected by multiplex and monoplex PCR for P. aeruginosa‐harbored plasmids. Mutation profile of sequenced MBL genes was screened using online software Clustal Omega. Out of 147 P. aeruginosa, 39 (26.5%) were carbapenem‐resistant isolates and 25 (64%) were confirmed to be positive for MBLs. The susceptibility rate of P. aeruginosa toward polymyxin B and norfloxacin was 99% and 88%, respectively. Identification of collected isolates by API analysis and constructed phylogenetic tree of 16S rRNA showed that the isolates were related to P. aeruginosa species. The frequency of blaGIM‐1, blaSIM‐1, and blaSPM‐1 was 52%, 48%, and 24%, respectively. BlaVIM and blaIMP‐like genes were 20% and 4% and the sequences confirm the isolate to be blaVIM‐1, blaVIM‐2, blaVIM‐4, and blaIMP‐1. Three mutations were identified in blaVIM‐4 gene. Our study emphasizes the high occurrence of multidrug‐resistant P. aeruginosa‐producing MBL enzymes.     

Tandem pore domain K+‐channel TASK‐3 (KCNK9) and idiopathic absence epilepsies

Recently, the gene coding for the tandem pore domain K⁺‐channel TASK‐3 (KCNK9) has been localized to the chromosomal region 8q24. Because mutations in ion channel genes have been recognized as an important factor in the etiology of abnormal neuronal excitability, TASK‐3 is an interesting candidate gene for epilepsies linked to 8q24. We therefore performed a mutation analysis of the TASK‐3 gene in 65 patients with childhood and juvenile absence epilepsy. Only one silent nucleotide exchange (636C/T) was detected in exon 2 of the TASK‐3 coding region. No evidence for an allelic association was found between the exon 2 polymorphism and absence epilepsy. Accordingly, genetic variation of the TASK‐3 coding region does not play a major role in the etiology of idiopathic absence epilepsies. © 2002 Wiley‐Liss, Inc.     

TFE3‐rearranged hepatic epithelioid hemangioendothelioma—a case report with immunohistochemical and molecular study

A recurrent YAP1‐TFE3 gene fusion has been identified in WWTR1‐CAMTA1‐negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver. We present the first case of TFE3‐rearranged hepatic epithelioid hemangioendothelioma in a 39‐year‐old Taiwanese woman. Computed tomography scan revealed multifocal, ill‐defined nodules involving both hepatic lobes. She then underwent deceased donor liver transplantation. Histologically, the tumors in the liver explant showed a biphasic growth pattern. One component was composed of dilated and well‐formed blood vessels lined by epithelioid cells with abundant eosinophilic cytoplasm, mimicking an alveolar pattern, whereas the other component was composed of cords and single cells, featuring intracytoplasmic vacuoles, separated by a myxoid stroma. The tumor cells showed vesicular nuclei and small indistinct nucleoli with mild to moderate cytologic atypia. Most tumor cells showed factor VIII, CD34, CD31, and TFE3 positivity in immunohistochemical study. Fluorescence in situ hybridization analysis for the tumor cells exhibited TFE3 gene rearrangement. The patient is currently alive, and no post‐operative tumor recurrence developed during a 13‐year follow‐up. Awareness of this rare vasoformative variant and identification of the gene rearrangement would be helpful on differential diagnosis with other high‐grade carcinoma and angiosarcoma of liver.     

Twenty‐four‐hour motor activity and body temperature patterns suggest altered central circadian timekeeping in Smith–Magenis syndrome,a neurodevelopmental disorder

Smith–Magenis syndrome (SMS) is a contiguous gene syndrome linked to interstitial microdeletion, or mutation of RAI1, within chromosome 17p11.2. Key behavioral features of SMS include intellectual disability, sleep‐disturbances, maladaptive, aggressive and self‐injurious behaviors, hyperactivity, and sudden changes in mood. A distinguishing feature of this syndrome is an inverted pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels. As the central circadian clock controls the 24‐hr rhythm of melatonin, we hypothesized that the clock itself may contribute to the disrupted pattern of melatonin and sleep. In this report, 24‐hr patterns of body temperature, a surrogate marker of clock‐timing, and continuous wrist activity were collected to examine the links between body temperature, sleep behavior, and the circadian clock. In addition, age‐dependent changes in sleep behavior were explored. Actigraphy‐estimated sleep time for SMS was 1 hr less than expected across all ages studied. The timing of the 24‐hr body temperature (Tb‐24) rhythm was phase advanced, but not inverted. Compared to sibling (SIB) controls, the SMS group had less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final awake times, increased waking after sleep onset (WASO), and increased daytime nap duration. The timing of wake onset varied with age, providing evidence of ongoing developmental sleep changes from childhood through adolescence. Clarification of the circadian and developmental factors that contribute to the disrupted and variable sleep patterns in this syndrome will be helpful in identifying more effective individualized treatments.     

Changes in calsequestrin,TNF‐α, TGF‐β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps,diaphragm and intrinsic laryngeal muscles

In Duchenne muscular dystrophy (DMD), the search for new biomarkers to follow the evolution of the disease is of fundamental importance in the light of the evolving gene and pharmacological therapies. In addition to the lack of dystrophin, secondary events including changes in calcium levels, inflammation and fibrosis greatly contribute to DMD progression and the molecules involved in these events may represent potential biomarkers. In this study, we performed a comparative evaluation of the progression of dystrophy within muscles that are differently affected by dystrophy (diaphragm; DIA and quadriceps; QDR) or spared (intrinsic laryngeal muscles) using the mdx mice model of DMD. We assessed muscle levels of calsequestrin (calcium‐related protein), tumour necrosis factor (TNF‐α; pro‐inflammatory cytokine), tumour growth factor (TGF‐β; pro‐fibrotic factor) and MyoD (muscle proliferation) vs. histopathology at early (1 and 4 months of age) and late (9 months of age) stages of dystrophy. Fibrosis was the primary feature in the DIA of mdx mice (9 months: 32% fibrosis), which was greater than in the QDR (9 months: 0.6% fibrosis). Muscle regeneration was the primary feature in the QDR (9 months: 90% of centrally nucleated fibres areas vs. 33% in the DIA). The QDR expressed higher levels of calsequestrin than the DIA. Laryngeal muscles showed normal levels of TNF‐α, TGF‐β and MyoD. A positive correlation between histopathology and cytokine levels was observed only in the diaphragm, suggesting that TNF‐α and TGF‐β serve as markers of dystrophy primarily for the diaphragm.     

GABA‐A receptor β3 and α5 subunit gene cluster on chromosome 15q11–q13 and bipolar disorder: A genetic association study

There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA‐A receptor α5 subunit gene locus (GABRA5) on chromosome 15q11–of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor β3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM‐IV and ICD‐10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy‐Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA‐repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA‐repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease. © 2001 Wiley‐Liss, Inc.