Disorders of Developmental Biology

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Homo sapiens
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Developmental disorders affect formation of body organs and organ systems. The causes of defects in human development are diverse and incompletely understood, and include environmental insults such as nutrient deficiency, exposure to toxins and infections (Gilbert 2000, National Research Council (US) Committee on Developmental Toxicology 2000, Taylor and Rogers 2005, Zilbauer et al. 2016, Izvolskaia et al. 2018), as well as genetic causes such as aneuploidy and other chromosomal abnormalities, and germline mutations in genes that regulate normal development. It is estimated that about 40% of human developmental disabilities can be attributed to genetic aberrations (Sun et al. 2015), of which at least 25% are due to mutations affecting single genes (Chong et al. 2015), and this latter group of Mendelian developmental disorders is the focus of curation in Reactome.

Disorders of nervous system development affect the function of the central nervous system (CNS) and impair motor skills, cognition, communication and/or behavior (reviewed by Ismail and Shapiro 2019). So far,we have annotated the role of loss-of-function mutations in methyl-CpG-binding protein 2 (MECP2), an epigenetic regulator of transcription, in Rett syndrome, a pervasive developmental disorder (Pickett and London 2005, Ferreri 2014).

Disorders of myogenesis are rare hereditary muscle diseases that in the case of congenital myopathies are defined by architectural abnormalities in the muscle fibres (Pelin and Wallgren-Pettersson 2019, Phadke 2019, Radke et al. 2019, Claeys 2020) and in the case of muscular dystrophies by increased muscle breakdown that progresses with age (Pasrija and Tadi 2020). Mutations in cadherin family genes are present in some types of muscular dystrophy (Puppo et al. 2015).

Disorders of pancreas development result in pancreatic agenesis, where a critical mass of pancreatic tissue is congenitally absent. For example, the PDX1 gene is a master regulator of beta cell differentiation and homozygous deletions or inactivating mutations in PDX1 gene cause whole pancreas agenesis. PDX1 gene haploinsufficiency impairs glucose tolerance and leads to development of diabetes mellitus (Hui and Perfetti 2002, Babu et al. 2007, Chen et al. 2008).

Left-right asymmetry disorders are caused by mutations in genes that regulate the characteristic asymmetry of internal organs in vertebrates. Normally, cardiac apex, stomach and spleen are positioned towards the left side, while the liver and gallbladder are on the right. Loss-of-function mutations in the CFC1 gene, whose protein product functions as a co-factor in Nodal signaling, result in heterotaxic phenotype in affected patients, manifested by randomized organ positioning (Bamford et al. 2000).

Congenital lipodystrophies are characterized by a lack of adipose tissue, which predisposes affected patient to development of insulin resistance and related metabolic disorders. The severity of metabolic complications is correlates with the extent of adipose tissue loss. Loss-of-function mutations in the PPARG gene, encoding a key transcriptional regulator of adipocyte development and function, are a well-established cause of familial partial lipodystrophy type 3 (FPLD3) (Broekema et al. 2019).

Congenital stem cell disorders are caused by mutations in genes that regulate the balance between stem cells maintenance and commitment to differentiated lineages. Loss-of-function mutations in the SOX2 gene, which encodes a transcription factor involved in the maintenance of totipotency during embryonic preimplantation period, pluripotency of embryonic stem cells, and multipotency of neural stem cells, are the cause of anophthalmia (the absence of an eye) and microphthalmia (the presence of a small eye within the orbit (Verma and Fitzpatrick 2007, Sarlak and Vincent 2016).

HOX-related structural birth defects are caused by loss-of-function mutations in HOX family genes.HOX transcription factors play a fundamental role in body patterning during embryonic development, and HOX mutation are an underlying cause of many congenital limb malformations (Goodman 2002).

Congenital keratinization disorders are caused by dominant negative mutation in keratin genes and depending on where the affected keratin gene is expressed, they affect epithelial tissues such as skin, cornea, hair and/or nails (McLean and Moore 2011).

Disorders of immune system development are caused by mutations in genes that regulate differentiation of blood cell lineages involved in immune defense, leading to immune system defects. For example, mutations in the gene encoding CSF3R, a receptor for the granulocyte-colony stimulating factor, result in congenital neutropenia, characterized by a maturation arrest of granulopoiesis at the level of promyelocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections from an early age and may be predisposed to myelodysplastic syndromes or acute myeloid leukemia (Germeshausen et al. 2008; Skokowa et al. 2017).

Literature References
PubMed ID Title Journal Year
30742913 Gene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants

Kalkhoven, E, Broekema, MF, Savage, DB, Monajemi, H

Biochim Biophys Acta Mol Cell Biol Lipids 2019
31060728 Recently Identified Congenital Myopathies

Radke, J, Goebel, HH, Stenzel, W

Semin Pediatr Neurol 2019
11062482 Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects

Goodship, JA, Towbin, J, Ferrero, GB, Burdine, RD, Splitt, M, dela Cruz, J, Bowers, P, Casey, B, Saplakoğlu, U, Shen, MM, Marino, B, Schier, AF, Muenke, M, Bamford, RN, Roessler, E

Nat. Genet. 2000
32644382 Congenital Muscular Dystrophy

Pasrija, D, Tadi, P

31060726 Myopathology of Congenital Myopathies: Bridging the Old and the New

Phadke, R

Semin Pediatr Neurol 2019
21890491 Keratin disorders: from gene to therapy

Moore, CB, McLean, WH

Hum. Mol. Genet. 2011
24855782 [Pervasive developmental disorders]

Ferreri, M

Rev Prat 2014
31116115 What are neurodevelopmental disorders?

Shapiro, BK, Ismail, FY

Curr. Opin. Neurol. 2019
25691455 The Roles of the Stem Cell-Controlling Sox2 Transcription Factor: from Neuroectoderm Development to Alzheimer's Disease?

Sarlak, G, Vincent, B

Mol. Neurobiol. 2016
15845126 Practitioner review: early adversity and developmental disorders

Taylor, E, Rogers, JW

J Child Psychol Psychiatry 2005
12357469 Limb malformations and the human HOX genes

Goodman, FR

Am. J. Med. Genet. 2002
18039390 Anophthalmia and microphthalmia

FitzPatrick, DR, Verma, AS

Orphanet J Rare Dis 2007
25615407 Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype

Gaildrat, P, Krahn, M, Dionnet, E, Hayashi, Y, Magdinier, F, Nishino, I, Lévy, N, Goto, K, Bernard, R, Vovan, C, Helmbacher, F, Attarian, S, Bertaux, K, Puppo, F, Bartoli, M, Castro, C, Gaillard, MC

Hum. Mutat. 2015
30469423 Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects

Zakharova, L, Sharova, V, Izvolskaia, M

Int J Mol Sci 2018
  Scientific Frontiers in Developmental Toxicology and Risk Assessment

National Research Council (US) Committee on Developmental Toxicology, Consortium

  Genetic Testing for Developmental Disabilities, Intellectual Disability, and Autism Spectrum Disorder

Schoelles, KM, Hakonarson, H, Fontanarosa, J, Levy, SE, Sun, F, Oristaglio, J, Sullivan, N

16254487 The neuropathology of autism: a review

Pickett, J, London, E

J. Neuropathol. Exp. Neurol. 2005
26628441 Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives

Auricchio, R, Wirth, S, Heuschkel, R, Embleton, N, Gasparetto, M, Greco, L, Zilbauer, M, Jenke, A, Galatola, M, Postberg, J, Zellos, A, Kraiczy, J

J. Pediatr. Gastroenterol. Nutr. 2016
18536571 G-CSF receptor mutations in patients with congenital neutropenia

Ballmaier, M, Welte, K, Germeshausen, M, Skokowa, J, Zeidler, C

Curr. Opin. Hematol. 2008
28593997 Severe congenital neutropenias

Welte, K, Skokowa, J, Dale, DC, Zeidler, C, Touw, IP

Nat Rev Dis Primers 2017
31060721 Update on the Genetics of Congenital Myopathies

Pelin, K, Wallgren-Pettersson, C

Semin Pediatr Neurol 2019
11834421 Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Hui, H, Perfetti, R

Eur. J. Endocrinol. 2002
31578728 Congenital myopathies: an update

Claeys, KG

Dev Med Child Neurol 2020
26166479 The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities

Chakravarti, A, Patterson, KE, Leal, SM, Bamshad, MJ, Watkins, L, Hamosh, A, Ling, H, Gunel, M, Hoover-Fong, J, Muzny, D, Doheny, K, Hetrick, K, Wiszniewski, W, Blue, E, Mane, S, Avramopoulos, D, Sobreira, N, Lifton, RP, Smith, JD, Valle, D, Boerwinkle, E, Witmer, PD, Chong, JX, Gambin, T, Nickerson, DA, Scott, AF, Tabor, HK, Kircher, M, Jhangiani, SN, Bilguvar, K, Centers for Mendelian Genomics, -, Gibbs, RA, Boehm, C, Buckingham, KJ, Lupski, JR, Mathews, D, Harrell, TM, Coban Akdemir, ZH, Sutton, VR, Reinier, F, McMillin, MJ, Shendure, J, López-Giráldez, F

Am. J. Hum. Genet. 2015
18519458 Neonatal and late-onset diabetes mellitus caused by failure of pancreatic development: report of 4 more cases and a review of the literature

Al-Ali, M, Dattani, MT, Hussain, K, Marsh, P, Hindmarsh, P, Jones, PM, Chen, R

Pediatrics 2008
17659992 A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Deering, TG, Babu, DA, Mirmira, RG

Mol. Genet. Metab. 2007
  Developmental Biology, 6th edition

Gilbert, F

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disease DOID:4
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