Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel–Feil syndrome

Abstract

Klippel–Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel–Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel–Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left–right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel–Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel’s deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel–Feil syndrome, and in addition—from a mechanistic standpoint—suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy.

Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies

“…Mutation of MESP2 also causes another autosomal‐recessive disorder, spondylothoracic dysostosis, which is radiologically distinct from SCDO2, with multiple defects in vertebral malformation and spine formation, as well as bilateral fusions of the ribs at the costovertebral junctions, leading to a characteristic “crab‐like” appearance of the thorax [Cornier et al., ]. A recent finding indicated that RIPPLY2 is also involved in a milder form of SDV, autosomal‐recessive Klippel–Feil syndrome (KFS), characterized by short neck with reduced neck movement and low posterior hairline resulting from fusion of the cervical spine [Karaca et al., ]. Autosomal‐recessive KFS has been associated with homozygous‐truncating mutations in MEOX1 (MIM# 600147) and MYO18B (MIM# 607295) [Bayrakli et al., ; Mohamed et al., ; Alazami et al., ].…”

Proximal Deletion of 6q Overlapping with Toriello-Carey Facial Phenotype: Prenatal Findings, Clinical Course, Differential Diagnosis, and Review

“…TBX6 is a key element in the process of somitogenesis and is also involved in congenital scoliosis [Wu et al, 2015]. In addition, recessive mutations in RIPPLY2 cause vertebral segmentation defects as Klippel-Feil syndrome [Karaca et al, 2015].…”

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

“…Five of the six types of SCDO identified to date are caused by recessive mutations in core Notch signaling pathway components and downstream target genes: SCDO1; DLL3 (OMIM #277300)[319], SCDO2; MESP2 (Mesoderm posterior bHLH transcription factor 2, Notch target gene, OMIM #608681)[320], SCDO3; LFNG (OMIM #609813)[321], SCDO4; HES7 (Notch target gene, OMIM #613686)[322], and SCDO5; TBX6 (T-box 6 , Notch target gene [323,324], OMIM #122600, autosomal dominant forms have also been reported)[325,326]. The sixth SCDO gene, RIPPLY2 (Ripply transcriptional repressor 2 , OMIM #616566), lies downstream of the pathway and regulates the expression and/or function of MESP2 and TBX6[327]. In mice, many of these genes have been shown to play a critical role in somitogenesis [328,329], indicating that SCDO is caused by misregulation of an evolutionarily conserved transcriptional pathway that regulates somite (precursor of vertebra and other tissues) formation[330,331].…”