X‐linked brachytelephalangic chondrodysplasia punctata: A simple trait that is not so simple

Casarin, Alberto; Rusalen, Francesca; Doimo, Mara; Trevisson, Eva; Carraro, Silvia; Clementi, Maurizio; Tenconi, Romano; Baraldi, Eugenio; Salviati, Leonardo

doi:10.1002/ajmg.a.33039

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…Mutations in the ARSE gene cause X-linked brachytelephalangic chondrodysplasia punctata ( CDPX1 ; OMIM #302950), a congenital disorder of bone and cartilage development also characterized by short stature [12]. The co-localization of human growth syndrome genes with SNPs associated with adult height has been reported in European-ancestry samples [3], [13], [14].…”

Section: Resultsmentioning

confidence: 99%

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

et al. 2011

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Adult height is a classic polygenic trait of high heritability (h 2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

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Section: Resultsmentioning

confidence: 99%

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

et al. 2011

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“…Calcification in these disorders can be either diffuse or punctate. Stippled epiphyses have typically been considered a necessary criterion for CDPX1 diagnosis, but Casarin et al [ reported on a 14‐month‐old boy with ARSE deletion who did not have stippled epiphyses. Stippled epiphyses have also been reported in patients with KS [Say et al, ; Cormode et al, ; Ziereisen et al, ] although not as commonly as in those with CDPX1.…”

Section: Discussionmentioning

confidence: 99%

“…However, eight of 29 reported patients with KS, including Patient 3 in this series, did not have congenital heart disease (reports by Miller [ and Munroe et al [ did not address cardiac evaluation and therefore these three patients are not included in the denominator). Diffuse tracheobronchial tree calcification and stenosis is a major cause of morbidity in patients with KS but has also been reported in at least two patients with ARSE ‐mutation associated CDPX1 [Wolpoe et al, ; Casarin et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…Like individuals with KS, individuals with CDPX1 have varying degrees of midface retrusion, short distal phalanges, and abnormal calcification. To date, ARSE mutations have been reported in 33 patients but there are many patients with clinical features of CDPX1 who do not have an ARSE mutation [Nino et al, ; Casarin et al, ]. There is a wide variety in severity ranging from neonatal lethality to complete lack of symptoms in males [Brunetti‐Pierri et al, ; Casarin et al, ].…”

Section: Introductionmentioning

confidence: 99%

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Keutel syndrome: Report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis

Weaver

Hallek

Hopkin

et al. 2014

American J of Med Genetics Pt A

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Keutel syndrome is a rare, autosomal recessive disorder characterized by diffuse cartilage calcification, peripheral pulmonary artery stenosis, midface retrusion, and short distal phalanges. To date, 28 patients from 18 families have been reported, and five mutations in the matrix Gla protein gene (MGP) have been identified. The matrix Gla protein (MGP) is a vitamin K-dependent extracellular protein that functions as a calcification inhibitor through incompletely understood mechanisms. We present the clinical manifestations of three affected siblings from a consanguineous Turkish family, in whom we detected the sixth MGP mutation (c.79G>T, which predicts p.E27X) and a fourth unrelated patient in whom we detected the seventh MGP mutation, a partial deletion of exon 4. Both mutations predict complete loss of MGP function. One of the patients presented initially with a working diagnosis of relapsing polychondritis. Clinical features suggestive of Keutel syndrome were also observed in one additional unrelated patient who was later found to have a deletion of arylsulfatase E, consistent with a diagnosis of X-linked recessive chondrodysplasia punctata. Through a discussion of these cases, we highlight the clinical overlap of Keutel syndrome, X-linked chondrodysplasia punctata, and the inflammatory disease relapsing polychondritis.

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“…Similarly, nine mothers of previously reported males with CDPX1 who had carrier testing were found to be carriers. 3,25,27 Maternal carriers were identified among both ARSE deletion and point mutation alleles (see Table 2). We suggest that the high frequency of maternal carriers, if proven, could be secondary to de novo mutations occurring more often in the germline of the maternal grandfather.…”

Section: Discussion Spectrum Of Arse Mutationsmentioning

confidence: 99%

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

Matos-Miranda

Nimmo

B³

et al. 2013

Genetics in Medicine

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Brachytelephalangic chondrodysplasia punctata (BCP) describes a group of heterogeneous conditions with overlapping phenotypes. X-linked recessive BCP (CDPX1) (OMIM no. 302950), originally recognized by Sheffield et al., 1 is a panethnic congenital rare disorder that affects males. The most characteristic clinical features are as follows: 2,3 (i) Chondrodysplasia punctata, or stippled epiphyses, observed on X-ray. These minimally involve the ankle and distal phalanges but can also include long bones, vertebrae, hips, costochondral junctions, hyoid bone, and tracheal and bronchial cartilage. Chondrodysplasia punctata can be observed initially in the second trimester of pregnancy by ultrasound but tends to improve or disappear by age 2-3 years. (ii) Brachytelephalangy, or shortening of the distal phalanges. A characteristic finding on X-ray is an inverted triangle appearance of the distal phalanges, with punctata on either side. (iii) Nasomaxillary hypoplasia, referring to absence or hypoplasia of the anterior nasal spine, causing a flat nasal base, reduced nasal tip protrusion, shortened columella, and vertical grooves within the alae nasi. (iv) Proportionate short stature. Another commonly observed characteristic is mixed conductive and sensorineural hearing loss. Most children have normal intellect and life span, but comorbidities can be present, including compression of the cervical spinal cord associated with cervical vertebral abnormalities or stenosis of the upper and lower airways that result from extensive calcifications within the tracheal and bronchial cartilage. 3,4 Intrafamilial differences in disease severity have also been documented. 3 The only known genetic cause of CDPX1 is defects in arylsulfatase E (ARSE). The ARSE gene is located at Xp22.3, within a cluster of contiguous arylsulfatase genes that share high sequence homology, escape X inactivation, and have pseudogenes on the Y chromosome. 5 There are 17 sulfatases in the human genome; all share extensive sequence homology and contain a highly conserved cysteine that undergoes a unique posttranslational modification essential for their catalytic activity. 6-8 ARSE is localized to the Golgi membranes, 9 and its transcript has been identified in multiple tissues. 5 Its protein product is a 589-amino-acid and 60 kD precursor, which is subject Purpose: The only known genetic cause of brachytelephalangic chondrodysplasia punctata is X-linked chondrodysplasia punctata 1 (CDPX1), which results from a deficiency of arylsulfatase E (ARSE). Historically, ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases. Methods:To further evaluate causes of brachytelephalangic chondrodysplasia punctata, we established a Collaboration Education and Test Translation program for CDPX1 from 2008 to 2010. Of the 29 male probands identified, 17 had ARSE mutations that included 10 novel missense alleles and one single-cod...

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X‐linked brachytelephalangic chondrodysplasia punctata: A simple trait that is not so simple

Cited by 10 publications

References 15 publications

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

Keutel syndrome: Report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

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