Expanding the clinical spectrum of recessive truncating mutations of<i>KLHL7</i>to a Bohring-Opitz-like phenotype

Bruel, Ange‐Line; Bigoni, Stefania; Kennedy, Joanna; Whiteford, Margo; Buxton, Chris; Parmeggiani, Giulia; Wherlock, Matthew; Woodward, Geoff; Greenslade, Mark; Williams, Maggie; St‐Onge, Judith; Ferlini, Alessandra; Garani, Giampaolo; Ballardini, Elisa; Bon, Bregje W.M. van; Acuña-Hidalgo, Rocío; Bohring, Axel; Deleuze, Jean‐François; Boland, Anne; Meyer, Vincent; Olaso, Robert; Ginglinger, Emmanuelle; Study, Ddd; Rivière, Jean‐Baptiste; Brunner, Han G.; Hoischen, Alexander; Newbury‐Ecob, Ruth; Faivre, Laurence; Thauvin‐Robinet, Christel; Thévenon, Julien

doi:10.1136/jmedgenet-2017-104748

Cited by 16 publications

(35 citation statements)

References 18 publications

(11 reference statements)

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“…Autosomal recessive KLHL7 variants were also found to be associated with Bohring-Opitz syndrome-like (BOS MIM#605039) characterized by intrauterine growth retardation (IUGR), failure to thrive, facial dysmorphism, camptodactyly, foot malformations and severe developmental delay. 54 60 Cold-induced sweating was reported in two unrelated individuals and another personally seen individual (Hahn, unpublished). 61 During development, survivors may present dental deterioration and progressive kyphoscoliosis.…”

Section: Cs/ciss-like Phenotypementioning

confidence: 97%

“…In accordance with this, two of our CS/CISS‐like individuals also show RP. Autosomal recessive KLHL7 variants were also found to be associated with Bohring‐Opitz syndrome‐like (BOS MIM#605039) characterized by intrauterine growth retardation (IUGR), failure to thrive, facial dysmorphism, camptodactyly, foot malformations and severe developmental delay . Recently, individuals with an overlapping phenotype of CS/CISS, BOS and/or RP caused by KLHL7 variants were identified.…”

Section: Differential Diagnosticmentioning

confidence: 99%

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Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

et al. 2019

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Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1

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Section: Cs/ciss-like Phenotypementioning

confidence: 97%

Section: Differential Diagnosticmentioning

confidence: 99%

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

et al. 2019

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“…Homozygous mutations in the kelch domains of KLHL7 have been reported Crisponi/CISS1-like phenotype (MIM #272430) in five individuals from four families of Turkish origin (Angius et al, 2016). Six more patients with pathogenic variants in BACK and kelch domains are reported with a phenotype described as Bohring-Opitz-like as they carried overlapping findings with Bohring-Opitz syndrome (Bruel et al, 2017). Here we report an individual with a homozygous novel in-frame deletion in the BTB domain of KLHL7 resulting in a combined phenotype of Crisponi/CISS1-like phenotype and Bohring-Opitz like syndrome.…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic c.181_183delTGT in BTB domain of KLHL7 is associated with overlapping phenotypes of Crisponi/CISS1-like and Bohring-Opitz like syndrome

Kanthi

Hebbar

Bielas

et al. 2019

European Journal of Medical Genetics

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Biallelic pathogenic variants in KLHL7 are known to result in Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) like phenotype and Bohring-Opitz-like syndrome. In this report, a trio whole-exome sequencing (WES) was performed in proband with cold-induced sweating, microcephaly, facial dysmorphism, spasticity, failure to thrive, pigmentary abnormalities of the retina, hypoplasia of corpus callosum and periventricular nodular heterotopia. A novel homozygous in-frame deletion was identified in exon 2 of KLHL7, affecting the BTB domain of the protein. Our findings expand the clinical and molecular spectrum of KLHL7-related disorders.

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“…There is one report in the literature of siblings with suspected BOS (Greenhalgh et al, ). However, recently, these siblings were determined to have mutations in KLHL7 , and therefore do not have BOS (Bruel et al, ).…”

Section: Introductionmentioning

confidence: 99%

Bohring‐Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother

Bedoukian

Copenheaver²,

Bale³

et al. 2018

American J of Med Genetics Pt A

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Bohring-Opitz syndrome (BOS) is characterized clinically by severe developmental delays, microcephaly, failure to thrive, and characteristic facial features (prominent eyes, facial nevus simplex [flammeus], and others). Most patients meeting the clinical criteria for BOS (MIM: 605039) have a de novo nonsense or frameshift variant in ASXL1. We report a case of BOS caused by a pathogenic ASXL1 variant inherited from a germline mosaic mother. The ASXL1 mutation was detected via trio exome sequencing. The sequencing data demonstrated that the variant was inherited maternally but that the maternal variant was underrepresented in comparison to the normal allele. These results suggested maternal mosaicism for the variant. Additional testing on the mother was performed on buccal cell DNA, which was also consistent with mosaicism. The mother had been reported to be healthy and the family history is unremarkable. This is the first report of BOS caused by a mutation inherited from an unaffected, presumed germline mosaic parent. This phenomenon has been reported for other traditionally de novo dominant disorders like CHARGE syndrome and Cornelia de Lange syndrome. This case emphasizes the need for accurate low but non-negative recurrence risk counseling for families with children with BOS and it impacts exome interpretation strategy.

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Expanding the clinical spectrum of recessive truncating mutations ofKLHL7to a Bohring-Opitz-like phenotype

Abstract: We have expanded the clinical spectrum of autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.

Cited by 16 publications

References 18 publications

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

Bi-allelic c.181_183delTGT in BTB domain of KLHL7 is associated with overlapping phenotypes of Crisponi/CISS1-like and Bohring-Opitz like syndrome

Bohring‐Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother

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