Novel mutations in PDE6A and CDHR1 cause retinitis pigmentosa in Pakistani families

AIM: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families. METHODS: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations’ functions. RESULTS: A novel homozygous frameshift mutation [NM_000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM_033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing. CONCLUSION: This study expands the spectrum of genetic variants for arRP in Pakistani families.

Case Report: A Case of Hailey–Hailey Disease Mimicking Condyloma Acuminatum and a Novel Splice-Site Mutation of ATP2C1 Gene

Hailey–Hailey disease (HHD) is a rare autosomal-dominant blistering disorder characterized by recurrent vesicular and erosive lesions at intertriginous sites. We described a 24-year-old male who presented with multiple bright red verrucous papules in his mons pubis, bilateral groins, scrotum, perineum, and crissum, clinically resembling condyloma acuminatum. The histopathology showed extensive acantholysis with the characteristic appearance of a dilapidated brick-wall. The mutation analysis revealed a novel splice-site mutation in the ATP2C1 gene. The patient was definitely diagnosed with HHD. The antibacterial treatments resulted in a dramatic improvement. Our findings help to broaden the understanding of clinical manifestations of HHD and improve the clinical diagnosis and treatment of this disease.

A Novel Disease-Causing ASPA Gene Mutation (c.432+1 G>C) in an Iranian Patient with Canavan Disease: A Case Report

Canavan disease is an autosomal recessive genetic disease and rare fatal childhood neurological disorder caused by mutations in the ASPA gene, which resulted in a catalytic deficiency of the ASPA enzyme that catalyzes the hydrolysis of NAA into aspartate and acetate. Herein, we report an Iranian patient diagnosed with Canavan disease with a novel splice-site mutation in the ASPA gene (NM_000049.4; c.432+1 G>C). This report is based on a homozygous c.432+1 G>C mutation in the ASPA gene identified from an Iranian patient. As a result, a novel homozygous pathogenic mutation on ASPA is the cause of disease in the patient.

CS-1 Cerebellar liponeurocytoma; Report of two cases with detailed metabolic, immunohistochemical, and genetic evaluations

Cerebellar liponeurocytoma (cLNC), World Health Organization grade II neoplasm, is a rare brain tumor characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC, as well as metabolic imaging characteristics, have been poorly studied. Two patients with lower vermian tumors were operated on with telovelar approach. Moderate methionine uptake in positron emission tomography was observed in both cases. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Vacuolate cells with displacement of nuclei suggested the lipid accumulation, which was further supported by immunohistochemical staining of S-100. Although the extent of lipidization was relatively low compared with the reported cLNC cases, the immunohistochemical findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA in one case detected a splice site mutation of the ATRX gene, which is the first observation in the literature. Neither chemotherapy nor radiotherapy were administered postoperatively in both cases. In one case with spinal dissemination, residual tumor demonstrated progression 7 months after the resection. Long term follow-up data of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and better understanding of the oncogenic pathway as well as the natural history of cLNC.

Case Report: A Novel LAMP2 Splice-Altering Mutation Causes Cardiac-Only Danon Disease

Danon disease (DD) is a rare glycogen storage lysosomal disorder caused by mutations in the LAMP2 gene. Patients with DD are usually characterized clinically by severe multisystem syndromes. We describe a specific family with a novel pathogenic splice-altering mutation in the LAMP2 gene (c.741+2T>C) with cardiac-only symptoms (frequent ventricular tachycardia, intraventricular block, and hypertrophic cardiomyopathy). Minigene assays were used to evaluate the consequence of the splice-site mutation in the LAMP2 gene. The results showed that the c.741+2T>C mutation led to extra 6-bp preservation of intron 5 at the junction between exons 5 and 6 during transcriptional processing of the mRNA, which creates a stop codon and truncated the LAMP2 protein to 248-amino-acid residues. The mutant LAMP2 protein was predicted to have a conformational change, lacks the important transmembrane domain, and subsequent protein destabilization.

Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease

Background and ObjectiveAlexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation.MethodsGenetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed.ResultsThe patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5′ end of the exon 4.DiscussionGFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Detecting RB1 gene mutations in retinoblastoma tumour of patients in Northern Vietnam in 2020

Retinoblastoma, a type of eye cancer in children, is mostly caused by inactivating mutations of both copies of the RB1gene. Early diagnosis and identification ofRB1 gene mutations would improve treatment outcomes and patients’ management. This study was performed on 10 tumour samples of retinoblastoma patients using the direct sequencing technique. 11 different mutations were found in 9 out of 10 tumour samples, including 6 nonsense mutations, 1 missense mutation, 1 splice site mutation, and 3 frameshift mutations with 1 novel mutation that has not been reported before. The MLPA method was required to identify large deletion mutations in the RB1gene and the study on more samples to provide a picture of RB1 gene mutations in Vietnamese retinoblastoma patients

Successful pregnancy after ovulation induction with human chorionic gonadotropin in a woman with selective luteinising hormone deficiency

Selective LH deficiency has been described in several men, but only in two women who presented normal pubertal development but secondary amenorrhoea due to anovulation. Despite its rarity, this condition represents a valuable model for studying the processes regulated by FSH or LH during late folliculogenesis and ovulation in humans. A woman previously diagnosed with selective LH deficiency due to a homozygous germline splice site mutation in LHB (IVS2 + 1G→C mutation) was submitted to an individualised ovarian induction protocol, first with recombinant LH and then with highly purified urinary hCG. Ovarian follicle growth and ovulation were achieved, and a healthy baby was born after an uneventful term pregnancy. The treatment described herein demonstrates that the clinical actions of exogenous LH or hCG in inducing late-stage follicular development in women with deficient LH production or performance might be interchangeable or inevitable, once FSH-dependent early follicular growth is assured.