Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes

Schaefer, Eric; Durand, Myriam; Stoetzel, Corinne; Doray, Bérénice; Viville, B.; Hellé, Sophie; Danse, Jean-Marc; Hamel, C.; Bitoun, Pierre; Goldenberg, Alice; Finck, Stefanie; Faivre, Laurence; Sigaudy, Sabine; Holder, Muriel; Vincent, Marie-Claire; Marion, Vincent; Bonneau, Dominique; Verloes, Alain; Nisand, I.; Mandel, Jean‐Louis; Dollfus, Hélène

doi:10.1016/j.ejmg.2010.10.004

Cited by 38 publications

(38 citation statements)

References 14 publications

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“…[3,4] The clinical spectrum shows overlap with a number of other genetic disorders involving abnormalities of ciliogenesis, such as McKusick-Kaufman syndrome and Alström syndrome. [5] Additional reports have expanded both the ocular and systemic phenotype. [6][7][8][9] BBS is typically an autosomal recessive disorder.…”

Section: To Prof Peter Beighton 'Do Genetics and See The World ' …mentioning

confidence: 99%

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Bardet Biedl syndrome in South Africa: A single founder mutation

et al. 2016

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Background. Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA.Method. This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. Results. A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.

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Section: To Prof Peter Beighton 'Do Genetics and See The World ' …mentioning

confidence: 99%

“…[10] Most of the genes code for proteins belonging to two functional groups. BBS 1,2,4,5,7,8 and 9 are responsible for the formation of a complex known as the BBSome, important in promoting ciliogenesis. BBS 6, 10 and 12 code for type II chaperonins, which contribute to assembly of the BBSome.…”

Section: To Prof Peter Beighton 'Do Genetics and See The World ' …mentioning

confidence: 99%

Bardet Biedl syndrome in South Africa: A single founder mutation

et al. 2016

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“…While renal malformations are frequently present in the fetal phase, additional pathognomonic features of BBS, such as obesity and retinitis pigmentosa, will only present later in life [17]. Nevertheless, there exists a substantial overlay in both genetics and prenatal malformations between these two syndromes [7]. Whereas MKKS patients remain free of late-onset complications, patients with BBS develop retinitis pigmentosa, obesity, renal dysfunction, and cognitive impairment that distinguish these two syndromes in infancy [5, 7, 18].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, there exists a substantial overlay in both genetics and prenatal malformations between these two syndromes [7]. Whereas MKKS patients remain free of late-onset complications, patients with BBS develop retinitis pigmentosa, obesity, renal dysfunction, and cognitive impairment that distinguish these two syndromes in infancy [5, 7, 18]. A substantial proportion of children initially diagnosed with MKKS are in fact patients with BBS, and consequently we categorized these fetuses within the MKKS/BBS spectrum.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas isolated hydro(metro)colpos is a rare disease, McKusick-Kaufman syndrome (MKKS) and Bardet-Biedl syndrome (BBS) are syndromes that include hydro(metro)colpos [5-7]. In individual cases, hydro(me tro)colpos has been described in fetuses with features of a VACTERL (vertebral, anal, cardiac, trachea-esophageal fistula, renal/kidney, limb defects) or MURCS (Mülleri an agenesis, renal agenesis, cervicothoracic, somite abnormalities) association [8], Herlyn-Werner-Wunder lich syndrome (HWWS), Langer-Giedion syndrome, or Pallister-Hall syndrome [9-11].…”

Section: Introductionmentioning

confidence: 99%

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Prenatal Diagnosis of Hydro(metro)colpos: A Series of 20 Cases

Mallmann¹,

Reutter²,

Mack-Detlefsen

et al. 2018

Fetal Diagn Ther

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Background: Hydrocolpos and hydrometrocolpos are rare malformations caused by accumulation of secretion due to congenital obstruction of the vagina. Hydro(metro)colpos may be isolated or can be combined with other malformations as part of a syndromic disorder. We report on a series of 20 cases with hydro(metro)colpos diagnosed prenatally, delineate the differential diagnoses, and illustrate the spectrum of associated malformations. Subjects and Methods: This was a retrospective study involving 20 fetuses with hydro(metro)colpos at two large tertiary referral centers in Germany over an 18-year period (2000–2017). Results: The median diagnosis was made at 30⁺⁴ weeks of gestation, the earliest at 20⁺⁶ weeks, the latest at 37⁺² weeks. All 20 fetuses presented with the typical cystic structure behind the fetal bladder. Additional malformations included urogenital malformations, hexadactyly, and heart defects. Postnatal follow-up revealed that hydro(metro)colpos was associated with anorectal malformation in 11/20 fetuses, McKusick-Kaufman syndrome or Bardet-Biedl syndrome in 4/20 fe tuses, Mayer-Rokitansky-Küster-Hauser syndrome in 3/20 fetuses, and Herlyn-Werner-Wunderlich syndrome in 1/20. In 1 fetus pressure from an intraabdominal teratoma resulted in prenatal hydro(metro)colpos. Conclusion: Hydro(me tro)colpos is a rare prenatal sonographic feature. Multidisciplinary prenatal counseling should include all potential syndromes that can present with hydro(metro)colpos in the prenatal setting.

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