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

Abstract

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...

Breaking TADs: How Alterations of Chromatin Domains Result in Disease

“…Without this barrier, an enhancer from a neighboring TAD is free to act on PITX1 thereby inducing expression in the fore-and hindlimb. Recently, a tandem duplication that relocates the PITX1 transcriptional unit in front of a strong forelimb enhancer was identified as the cause of Liebenberg syndrome [72].…”

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome

“…This is also observed in the human Liebenberg phenotype whereby the closer Pen is placed in a linear relation to PITX1 , the more complete the transformation of the arms into legs is 3 5. This is particularly evident in the duplication case that misplaces PITX1 only 10 kb from Pen, rather than the 400 kb linear distance in the wild type genome, creating the most severe arm-to-leg transformation documented 14. In line with this observation, the Pitx1 -Pen transgenic mouse shows strong ectopic expression of Pitx1 and severe forelimb malformation leading to loss of a zeugopodal elements and digits and the elbow joint displayed striking similarities to the knee joint) 3 5.…”

Design, construction, and advantages of 100% online laboratories in an upper division undergraduate biology course

“…The student is told that the DNA sequencing data revealed the presence of a mutation near Pitx1 in the human patient and that the identified mutation is in a region of the gene that may cause the gene to be aberrantly expressed in the forelimb (it is normally only expressed in the hindlimb). In humans, mutations in Pitx1 are associated with Liebenberg Syndrome [5][6][7]13]. These data suggest that these mutations may be responsible for Liebenberg Syndrome.…”

“…Liebenberg Syndrome is a unique condition where the arms of a person resemble their legs [4]. The transmission of the disease is autosomal dominant and mutations that can cause this disease has recently been identified [5][6][7]. However, students at this point in the laboratory were not informed that the underlying cause of this disease was known.…”