Novel sequence variants in the <i>MKKS</i> gene cause Bardet‐Biedl syndrome with intra‐ and inter‐familial variable phenotypes

Ullah, Asmat; Khalid, Maryam; Umair, Muhammad; Khan, Sher Alam; Bilal, Muhammad; Khan, Saadullah; Ahmad, Farooq

doi:10.1111/cga.12264

Cited by 13 publications

(12 citation statements)

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“…The two affected individuals from family 1 demonstrate classical features of BBS, including postaxial polydactyly, learning difficulties, retinitis pigmentosa, and truncal obesity (Beales et al., ; Kim, Fishman, Seiple, Szlyk, & Stone, ; Ullah et al., ). Interfamilial phenotypic variability was noted, with individual IV‐1 displaying more significant visual impairment and intellectual disability compared to his affected sister.…”

Section: Discussionmentioning

confidence: 99%

“…Functional studies have demonstrated diminished capacity of this mutant protein to stabilize the primary cilium, most likely the result of a defect in ciliary localization and protein interaction (Jacoby et al, 2009). The two affected individuals from family 1 demonstrate classical features of BBS, including postaxial polydactyly, learning difficulties, retinitis pigmentosa, and truncal obesity (Beales et al, 1999;Kim, Fishman, Seiple, Szlyk, & Stone, 2007;Ullah et al, 2017a). Interfamilial phenotypic variability was noted, with individual IV-1 displaying more significant visual impairment and intellectual disability compared to his affected sister.…”

Section: Discussionmentioning

confidence: 99%

“…BBS (OMIM 209900) is a rare genetically and clinically heterogeneous disorder, the primary features of which include intellectual disability, retinitis pigmentosa, postaxial polydactyly, obesity, renal dysfunction, and hypogonadism. Other variable features of BBS include dental anomalies, cardiovascular defects, hearing loss, speech impairment, diabetes mellitus, and other limb defects (Beales, Elcioglu, Woolf, Parker, & Flinter, 1999;Ullah et al, 2017aUllah et al, , 2017b. To date, pathogenic variants in 21 genes (BBS1-21) have been identified to cause BBS phenotypes in autosomal recessive or triallelic forms (Beales et al, 1999;Putoux, Attie-Bitach, Martinovic, & Gubler, 2012;Suspitsin & Imyanitov, 2016).…”

Section: Introductionmentioning

confidence: 99%

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BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

Khan

Lin

Harlalka

et al. 2019

Annals of Human Genetics

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Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole‐exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease‐causing variants within this setting enables the development of population‐specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

Khan

Lin

Harlalka

et al. 2019

Annals of Human Genetics

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“…In this patient, we also found Hutchinson‐like upper central incisors finding that were not previously defined in BBS6 patients (Figure 3). In other patients where this mutation was observed, the sign of Hutchinson‐like upper central incisors was not defined, although dental anomaly was identified (Denniston et al., 2014; Riazuddin et al., 2017; Ullah et al., 2018). Our Patient 4 is a 5‐year‐old male patient with obesity, polydactyly, severe ID, renal and genital anomalies.…”

Section: Discussionmentioning

confidence: 99%

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

Gümüş

Tunçez

Öz

et al. 2020

Annals of Human Genetics

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Background Bardet–Biedl syndrome (BBS) is a very‐rare autosomal recessive genetic disorder with severe multisystem manifestations. Genetic testing plays an important role in the early diagnosis of the disease. In this study, while trying to elucidate the genetic etiology of seven individuals with clinical BBS diagnosis from six different families, we also aimed to examine the distribution of BBS variations in this region of Turkey. Methods and materials Exome sequencing analysis is performed for clinically diagnosed patients with BBS in the present study followed by parental segregation. The unreported and previously described clinical features are presented. Results Homozygous variants, four of which are unreported, in BBS‐related genes (BBS5 [c.682‐2A > G], MKKS [c.775del], BBS7 [c.849+1G > T], BBS9 [c.965G > A], BBS10 [c.145C > T], LZTFL1[c.384G > A]) are detected for all the seven individuals included in the study. The most common clinical finding is polydactyly followed by renal anomalies. The clinical features not previously described are correlated to the unreported variant. Conclusions In this study, exome sequencing findings are discussed and four previously unreported disease‐associated variants are described including the fifth BBS‐implicated LZTFL1 change and possible genotype–phenotype correlation is described.

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“…It is categorized into two types: the postaxial type A (PAPA; well-developed extra digit) and the postaxial type B (PAPB; hypoplastic rudimentary extra digit or a skin tag or appears as a small protuberance). Polydactyly may occur as a non syndromic form (isolated) or in association with other severe abnormalities (syndromic form) such as Bardet-Biedl syn drome, split hand/foot malformation, syndactyly, and Ellis-Van Creveld syndrome, respectively (Khan et al, 2012;Ullah, Gul, et al, 2018;Ullah, Khalid, et al, 2018;Ullah, Umair, et al, 2017Umair, Ahmad, Bilal, & Abbas, 2018Umair, Ahmad, Bilal, Ahmad, & Alfadhel, 2018;Umair, Seidel, et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

Umair

Wasif

Albalawi

et al. 2019

Molec Gen & Gen Med

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Background Polydactyly is a common genetic limb deformity characterized by the presence of extra fingers or toes. This anomaly may occur in isolation (nonsyndromic) or as part of a syndrome. The disease is broadly divided into preaxial polydactyly (PPD; duplication of thumb), mesoaxial polydactyly (complex polydactyly), and postaxial polydactyly (PAP: duplication of the fifth finger). The extra digits may be present in one or both the limbs. Heterozygous variants in the GLI3 , ZRS / SHH , and PITX1 have been associated with autosomal dominant polydactyly, while homozygous variants in the ZNF141 , IQCE , GLI1 , and FAM92A have been associated with autosomal recessive polydactyly. Pathogenic mutations in the GLI3 gene (glioma‐associated oncogene family zinc finger 3) have been associated with both nonsyndromic and syndromic polydactyly. Methods Here, we report an extended five generation kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Whole‐exome sequencing followed by variant prioritization, bioinformatic studies, Sanger validation, and segregation analysis was performed. Results Using exome sequencing in the three affected individuals, we identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of the GLI3 encoding gene. Conclusion To the best of our knowledge, the present study reports on the first familial case of nonsyndromic postaxial polydactyly due to the GLI3 variant in Pakistani population. Our study also demonstrated the important role of GLI3 in causing nonsyndromic postaxial polydactyly.

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Novel sequence variants in the MKKS gene cause Bardet‐Biedl syndrome with intra‐ and inter‐familial variable phenotypes

Cited by 13 publications

References 6 publications

BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

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