Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Abstract

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes.The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

“…Short‐rib thoracic dysplasia, also known as asphyxiating thoracic dysplasia (ATD) or Jeune syndrome (SRTD (MIM# 208500)), is an autosomal recessive skeletal ciliopathy characterized by narrow thoracic cage, short ribs, shortened tubular bones, and a trident acetabular roof, with or without polydactyly and in some individuals renal, liver, and retinal involvement (Schmidts et al., ). Many genes have been associated with SRTD (Huber & Cormier‐Daire, ; Zhang et al., ) but to date only two individuals are reported with skeletal ciliopathies and pathogenic variants in IFT81 (Duran et al., ). MED (MIM# 132400) is a heterogeneous disorder of the epiphyses in the long bones, due to autosomal dominant heterozygous mutations in COMP, COL9A1, COL9A2, COL9A3 , or MATN3 (Jackson et al., ) or autosomal recessive homozygous mutations in SLC26A2 (Makitie et al., ) and CANT1 (Balasubramanian et al., ).…”

Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype?

“…Moreover, WES identified a homozygous missense variant (Chr11 (GRCh37) DYNC2H1 gene, with both parents being heterozygous carriers. This variant was previously reported in three patients with asphyxiating thoracic dysplasia (ATD) or short rib-polydactyly syndrome (SRPS) (Baujat et al, 2013;Dagoneau et al, 2009;Zhang et al, 2018). Particularly, only one 16-month-old patient (Baujat et al, 2013) had this variant in homozygosity; he showed clinical signs consistent with ATD as short ribs with narrow thorax, trident acetabular roof, long bones shortening, respiratory neonatal distress, long-term respirator complications, and short stature, so the DYNC2H1 variant was considered as disease causing by the authors.…”

Mutations in IFT80 cause SRPS Type IV. Report of two families and review

“…Most of the reported cases were ATD patients (Baujat et al, ; Beales et al, ). p.gly241Arg has been found in ATD (Zhang et al, ), as well as in Verma‐Naumoff syndrome (Cavalcanti et al, ) and Majewski syndrome (Zhang et al, ), p.Thr365Ala has been associated with ATD and BLS, and p.Leu163IlefsTer7 with BLS (Zhang et al, )…”

“…IFT80 is known to be involved in other ciliopathies, essentially in Jeune asphyxiating thoracic dysplasia (ATD) (Baujat et al, ; Beales et al, , 80; Zhang et al, ), but also in Verma‐Naumoff syndrome (Cavalcanti et al, ). Verma‐Naumoff syndrome has recently been subcategorized with Saldino‐Noonan syndrome as a single SRPS (SRPS Type I/III) by the current nosology (Bonafe et al, ).…”

“…The first identification of biallelic mutations in the IFT122 gene in a fetus with BLS was reported by Silveira et al in May 2017 (Silveira et al, ), although the skull deformity of this fetus was striking enough to evoke Sensenbrenner syndrome. In October 2017, Zhang et al identified a mutation in IFT80 in a fetus with features quite similar to BLS, although not thoroughly typical either and lacking some phenotypic delineation, (Zhang et al, ), suggesting some genetic heterogeneity for BLS. Here we describe novel mutations in the IFT80 gene segregating in two families with BLS, definitely confirming the inclusion of IFT80 in the molecular spectrum of the syndrome, and providing substantiating evidence that BLS was rightly classified as a ciliopathy.…”