A novel PTC mutation in the BTB domain of KLHL7 gene in two patients with Bohring-Opitz syndrome-like features

Abstract

The bric-a-brac, tramtrack and broad complex (BTB) superfamily of conserved proteins are involved in ubiquitinproteasome system that contains the Kelch-like (KLHL) gene family. Kelch-like family member 7 (KLHL7), one of the KLHL gene family, consists of one BTB/POZ domain, one BACK domain and five or six Kelch motifs. Numerous variants in KLHL7 gene domains have been reported with Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like features and retinitis pigmentosa 42, and have recently been identified as causing Bohring-Opitz syndrome (BOS)-like features. We report two siblings with BOS-like phenotype with healthy parents and living in Qazvin province (Central Iran). We performed whole-exome sequencing (WES) on the older patient and Sanger sequencing was carried out for validation of potential causative variants in the close family. A novel homozygous frameshift mutation, p.(Phe83Leufs*3), was identified in the BTB domain of KLHL7 that caused a premature translation-termination codon (PTC) in the two siblings with severe developmental delay, microcephaly, facial dysmorphism, peripheral retinal and optic disc atrophy and cardiac septal defects. Our findings are in agreement with the clinical spectrum of KLHL7 mutations, which are associated with BOSlike features that reports for first time in our population.

Clinical and molecular genetic findings of Crisponi/cold‐induced sweating syndrome (CS/CISS) spectrum in patients from Turkey

“…Short philtrum was rarely mentioned in the previous reports, 16,30 yet observable from the clinical photographs of the patients in both groups who survived infancy. 3,6,11,12,18,19,31 We suppose an unmentioned feature is kyphoscoliosis in KLHL7 cases, this non-ambulatory and severely retarded patients will probably develop kyphosis and/or scoliosis in older ages a feature not observed in our young cases. Cleft palate/bifid uvula was reported in only two patients with CRLF1 variants to date, and high and narrow palate associated with CRLF1 and KLHL7 cases was recorded in 38% and 56% of the patients, respectively.…”

“…Including the patients we here report, the incidence of cardiac involvement in CRLF1 and KLHL7 cases increased to 15%, 32,34,35,37,43 and 39%, respectively. 12,13,18 We observed peripheral pulmonary stenosis, a recognized cardiac defect in CRLF1-related phenotype, in a patient in the CRLF1 group. Interestingly, we also detected hypoplastic pulmonary artery and valvular pulmonary stenosis in a patient harboring a novel KLHL7 variant, indicating that pulmonary stenosis can be seen as a feature of both genes related with CS/CISS phenotypes.…”

“…To date, only 44 variants in CRLF1 were revealed in 88 patients in the literature, 26 of whom were from Turkey 8,15–17 . Regarding the variants of KLHL7 , only 13 have been identified in 21 patients so far, two of whom participated in the present study 11–13,18–21 …”

“…KLHL7 related phenotypes were most commonly identified in Turkey and Syria, followed by Iran and Italy, suggesting this CS/CISSrelated subtype is also more common in the Mediterranean region (Supplement Table 2). 11,12,18 CS/CISS phenotype is a spectrum of features with different ages of onset. The cracked soles of the previously reported Saudi Arabian cases with CRLF1 variants affecting residues on exon 6 were noted in childhood or adulthood.…”

“…8,[15][16][17] Regarding the variants of KLHL7, only 13 have been identified in 21 patients so far, two of whom participated in the present study. [11][12][13][18][19][20][21] In this study, we present the molecular basis of CS/CISS-like phenotypes in 23 clinically well-characterized patients, combining data gathered from two centers in Turkey. This report expands the clinical and molecular spectrum of CRLF1 and KLHL7-related disorders.…”