Disorders of Developmental Biology

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.

Disorders of myogenesis are rare hereditary muscle diseases that in the case of congenital myopathies are defined by architectural abnormalities in the muscle fibres and in the case of muscular dystrophies by increased muscle breakdown that progresses with age. Mutations in cadherin family genes are present in some types of muscular dystrophy.

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.

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.

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).

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.

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.

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.

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.