Human TBX1 Missense Mutations Cause Gain of Function Resulting in the Same Phenotype as 22q11.2 Deletions
TL;DR: It is concluded that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss of function mutations or deletions.
Abstract: Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.
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19 Nov 2015
TL;DR: The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease as mentioned in this paper.
Abstract: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness - all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.
1,850 citations
Journal Article•
TL;DR: 22q11.2 deletion syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome.
983 citations
TL;DR: A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter (1.5 mmol per liter) and his medical history is notable only for longstanding hearing difficulties.
Abstract: Copyright © 2008 Massachusetts Medical Society. A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter (1.5 mmol per liter) (normal range, 8.5 to 10.5 mg per deciliter [2.1 to 2.6 mmol per liter]), an albumin level of 3.9 g per deciliter, and a phosphorus level of 6.0 mg per deciliter (1.94 mmol per liter) (normal range, 2.5 to 4.5 mg per deciliter [0.81 to 1.45 mmol per liter]). His medical history is notable only for longstanding hearing difficulties. He reports no history of neck surgery and no throat tightness, muscle cramps, paresthesias, or seizures. His father and sister, who are both deceased, had kidney disease. On physical examination, both Chvostek’s and Trousseau’s signs are negative. His ionized calcium level is 0.75 mmol per liter (normal range, 1.10 to 1.32). How should his case be further evaluated and treated?
487 citations
TL;DR: How the advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD is explored.
Abstract: Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
484 citations
TL;DR: Chromosome 22q11.2 deletion syndrome is a common syndrome also known as DiGeorge syndrome and velocardiofacial syndrome, and the incidence is increasing due to affected parents bearing their own affected children.
423 citations
Cites background from "Human TBX1 Missense Mutations Cause..."
...This has also been seen in murine models and a gain-of-function TBX1 mutation.(85,173) The mechanism is not completely understood, but overexpression of TBX has been observed to downregulate the retinoic acid metabolic pathway....
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References
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TL;DR: The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters, and the majority of surviving patients were developmentally normal or had only mild learning problems.
Abstract: We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters.
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