Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Klopocki, Eva; Kähler, Christian M.; Foulds, Nicola; Shah, Hitesh; Joseph, Benjamin; Vogel, H.; Lüttgen, Sabine; Bald, R.; Besoke, Regina; Held, Karsten R.; Mundlos, Stefan; Kurth, Ingo

doi:10.1038/ejhg.2011.264

Cited by 49 publications

(35 citation statements)

References 21 publications

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“…However, the integrated sampling of numerous sites uncovered far more complex patterns of regulation operating across tissues. The enrichment of PITX1 binding motifs in active regulatory regions uniquely shared across limb bud and palate fits with mutations in PITX1 causing limb defects and cleft palate 30 . Similarly, GATA4 and GATA6, inferred from regulatory regions shared uniquely between heart and pancreas, are the only two TFs linked to the dual phenotype of cardiac malformation and monogenic diabetes 31,32 .…”

Section: Discussionsupporting

confidence: 55%

The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders

Gerrard

Berry

Jennings

et al. 2019

Preprint

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How the genome activates or silences transcriptional programmes governs organ 23 formation. Little is known in human embryos undermining our ability to benchmark the 24 fidelity of in vitro stem cell differentiation or cell programming, or interpret the pathogenicity 25 of noncoding variation. Here, we studied histone modifications across thirteen tissues during 26 human organogenesis. We integrated the data with transcription to build the first overview of 27 how the human genome differentially regulates alternative organ fates including by 28 repression. Promoters from nearly 20,000 genes partitioned into discrete states without 29 showing bivalency. Key developmental gene sets were actively repressed outside of the 30 appropriate organ. Candidate enhancers, functional in zebrafish, allowed imputation of 31 tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 32 noncoding mutations from patients with developmental disorders allowed correlation to 33 unanticipated target genes. Taken together, the data provide a new, comprehensive genomic 34 framework for investigating normal and abnormal human development. 35

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Section: Discussionsupporting

confidence: 55%

The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders

Gerrard

Berry

Jennings

et al. 2019

Preprint

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“…Interactions between different key factors, which when mutated lead to limb anomalies (modified from [Niswander, 2003]). FGF8 Long bone loss Browne et al [2012] FGF10 Total limb loss Sekine et al [1999] FGF10 Long bone loss Browne et al [2012] Femur loss or hypoplasia Pitx1/2 Femoral a-or hypoplasia Marcil et al [2003] PITX1 Tibial loss Gurnett et al [2008]; Klopocki et al [2012] Tbx4 Femoral hypoplasia Naiche and Papaioannou [2007] TBX4 Small patella Bongers et al [2004]; Kerstjens-Frederikse et al [2013] Hoxa10/Hoxc10/…”

Section: Discussionmentioning

confidence: 99%

“…Zeugopod shortening Wellik and Capecchi [2003] Shh Shh and Alx4 Zeugopod shortening te Welscher et al [2002] SHH Tibial hemimelia Cho et al [2013] SHH Long bone absence Browne et al [2012] ALX3/ALX4 Tibial aplasia Wechsler et al [2004] Tibia loss or shortening Pitx1/2 Tibial a-or hypoplasia Marcil et al [2003] PITX1 Tibial loss Gurnett et al [2008]; Klopocki et al [2012] Wnt7a Tibial loss or shortening Parr and McMahon [1995] WNT7 Phalangeal and tarsal shortening Woods et al, 2006] HOXB Tibial shortening Maraia et al [1991] HOXD Tibial/fibular hypoplasia Dlugaszewska et al [2006] Fibula loss or shortening homozygous mice manifest shortened distal toe phalanges [Hummel, 1970], Gli3 knockouts exhibit absent tibia and bowing fibula in the presence of Hoxd12 transgene , whereas Hoxc11 overexpressing mice have absent ulna and fibula [Papenbrock et al, 2000]. Hoxa11/Hoxd11 double knockout mice feature an almost total ulnar and radial loss [Davis et al, 1995], and transgenic mice expressing Hoxa9, Hoxd11, Hoxa13, and Hoxd13 using Prx1 promoter [Williams et al, 2006] have progressive shortening of the stylopod and/or zeugopod.…”

Section: Hoxd11mentioning

confidence: 99%

Isolated bilateral transverse agenesis of the distal segments of the lower limbs at the level of the knee joint in a human fetus

Christiaens

Deprez

Amyere

et al. 2015

American J of Med Genetics Pt A

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Congenital limb anomalies occur in Europe with a prevalence of 3.81/1,000 births and can have a major impact on patients and their families. The present study concerned a female fetus aborted at 23 weeks of gestation because she was affected by non-syndromic bilateral absence of the zeugopod (leg) and autopod (foot). Autopsy of the aborted fetus, X-ray imaging, MRI, and histochemical analysis showed that the distal extremity of both femurs was continued by a cartilage-like mass, without joint cavitation. Karyotype was normal. Moreover, no damaging variant was detected by exome sequencing. The limb characteristics of the fetus, which to our knowledge have not yet been reported in humans, suggest a developmental arrest similar to anomalies described in chicks following surgical experiments on the apical ectodermal ridge of the lower limbs.

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“…They proposed that the nearby enhancer HS1473 is then free to act on PITX1 resulting in fore limb expression of PITX1 . By contrast, mutations of PITX1 or haploinsufficency of PITX1 cause a spectrum of lower limb malformations including mirror‐image polydacytly and autosomal dominant club foot [Klopocki et al, ].…”

Section: To the Editormentioning

confidence: 99%

A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome

Seoighe

Gadancheva

Regan

et al. 2014

American J of Med Genetics Pt A

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TO THE EDITOR:Liebenberg [1973] reported a five-generation family with an autosomal dominant inheritance of upper limb deformities. Liebenberg syndrome results from structural aberrations in the regulatory landscape of PITX1 [Spielmann et al., 2012]. Previous reported patients all have resulted from deletions within the region [Spielmann et al., 2012;Al-Qattan et al., 2013]. One recent patient had a deletion adjacent to, but not including, PITX1 [Mennen et al., 2013].Alterations in this regulatory landscape can lead to disruption and ectopic expression of PITX causing a homeotic transformation leading to arthrogrypotic deformities of the upper limbs which resemble lower limbs in phenotype [Spielmann et al., 2012]. The three major components of this phenotype include brachydactyly, abnormal morphology of the carpal bones, and elbow dysgenesis and there is great variability in phenotypic expression. In early development, the upper and lower limb bud morphology is similar. Differentiation into lower limb results from expression of specific transcription factors including PITX1, TBX4, and HOX10 which are normally only expressed in the lower limbs [Logan and Tabin, 1999; Logan, 2009, 2011a,b;Butterfield et al., 2010]. Structural changes have been found to remove a cis-regulatory active boundary element, thereby moving the active enhancer elements in the vicinity of PITX1 [Spielmann et al., 2012]. They proposed that the nearby enhancer HS1473 is then free to act on PITX1 resulting in fore limb expression of PITX1. By contrast, mutations of PITX1 or haploinsufficency of PITX1 cause a spectrum of lower limb malformations including mirror-image polydacytly and autosomal dominant club foot ].We present a child who had a de novo gain at chromosome 5q31.1 including PITX1 with a severe manifestation of the syndrome which necessitated multiple operations. This is the first report of a gain within the region causing Liebenberg syndrome and confirms that it is disruption of regulatory regions rather than copy number variation that determines the Liebenberg phenotype.The propositus, a male, was born, weighing 4.1 kg (75th-91st centile) to a 29-year-old healthy primigravid mother and a 35-yearold father. The parents were healthy, non-consanguineous, and their family histories were non-remarkable. The pregnancy was uneventful and there was no history of maternal illnesses or exposures. Vaginal delivery was induced at 41 þ 3 weeks gestation and forceps assistance was required. Severe deformity of the upper limbs was noted at birth. No abnormalities of his lower limbs were noted. He was referred and seen at a joint congenital upper limb clinic at age 15 months. On examination, he had bilateral flexion deformity of the wrists, small, stiff digits with camptodactyly of his right ring, and little fingers (Fig. 1). He had good shoulder movement, a passive range of movement of his elbows of 75-90 degrees with his forearms held in pronation with limited supination. He had significant radial deviation of his wrists. Pincer grasp was limite...

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Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Cited by 49 publications

References 21 publications

The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders

The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders

Isolated bilateral transverse agenesis of the distal segments of the lower limbs at the level of the knee joint in a human fetus

A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome

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