Molecular insight into CREBBP and TANGO2 variants causing intellectual disability.

BACKGROUND: Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder. METHODS: Exome sequencing was used to identify the disease-causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. RESULTS: In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function. CONCLUSIONS: RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations.

USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families.

BACKGROUND: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20-30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants. METHODS: We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families. RESULTS: Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT. CONCLUSIONS: This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

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.

Comparison of Psoralen ultraviolet A (PUVA) photochemotherapy plus topical corticosteroids with PUVA plus bland emollients in the treatment of psoriasis.

BACKGROUND: Psoralen Ultraviolet A (PUVA) therapy is a well-established treatment of psoriasis. The objective of the study was to compare the clinical improvement in psoriasis with PUVA photochemotherapy + topical corticosteroids and PUVA + bland emollients. METHODS: Forty patients with chronic plaque type of psoriasis were divided into two equal groups each having 20 patients. PUVA therapy was given thrice weekly. In addition, patients of group-A were allowed to apply topical betamethasone 17-valerate 0.1% diluted 1 into 2 parts with plain vaseline twice daily. Patients of group-B were allowed to apply only plain vaseline over lesions twice daily. Clinical improvement in lesions was observed by decrease in the severity of erythema, scaling and plaque elevation. RESULTS: Clearance of psoriasis was achieved in 95%, of the patients treated with PUVA plus topical corticosteroids while clearance was achieved in 80% of patients treated with PUVA plus bland emollients (P = 0.0758). Median numbers of exposures for group-A were 16 & for group-B were 17.5 (p = 0.1029). Similarly, median cumulative dose in group-A was 64.5 J/cm2 & in group-B was 70.7 J/cm2 (p = 0.372). CONCLUSION: There is no significant difference in clinical improvement in psoriasis treated either by PUVA plus topical steroids or PUVA plus bland emollients.

Comparative efficacy of psoralen - UVA photochemotherapy versus narrow band UVB phototherapy in the treatment of psoriasis.

OBJECTIVE: To compare the clinical improvement in psoriasis with psoralen - UVA photochemotherapy versus narrow band UVB phototherapy alone. DESIGN: An interventional quasi- experimental study. PLACE AND DURATION OF STUDY: Dermatology Department, Nishtar Hospital, Multan, from May 2002 to June 2003. PATIENTS AND METHODS: Forty patients with chronic plaque type psoriasis were included in the study. These were divided into two equal groups each having 20 patients. PUVA or UVB therapy was given thrice weekly. Clinical improvement in lesions was observed by decrease in the severity of erythema, scaling and plaque elevation. RESULTS: Clearance of psoriasis was achieved in significantly greater proportion of patients treated with PUVA (85%) than with UVB phototherapy (60%) (p=0.03814). Significantly fewer number of exposures were required for clearance with PUVA (median number of treatments=17) as compared to UVB (median number of treatments=25.5) (p=0.0002). Median cumulative dose for PUVA was 69.1 J/cm2 and for UVB was 34.15 J/cm2, respectively (p<0.0001). CONCLUSION: When given thrice weekly, PUVA was more effective treatment for psoriasis than narrow band UVB phototherapy.