12q21 deletion syndrome: Narrowing the critical region down to 1.6 Mb including SYT1 and PPP1R12A

Abstract

Deletions in the 12q21 region are rare and non‐recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2–3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short‐upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A.

Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing

“…Another gene related to the Wnt pathway was PPP1R12A , which was identified as a putative cofactor of NKX2.5 ( 32 ). It encoded a regulatory subunit of myosin phosphatase and was related to significant roles in several cellular processes, such as gene expression regulation, cell cycle, and embryonic development ( 33 ). The knockdown of PPP1R12A enhanced cardiomyogenesis and rescued Wnt3a-mediated inhibition in mice embryonic stem cells ( 32 ).…”

A New 12q21 Deletion Syndrome: A Case Report and Literature Review

“…Several molecular mutations have been reported in other patients. 1 2 3 4 5 6 7 8 9 10 11 12 Common features included development delay, clinical dysmorphism, heart defects, and anomalies in the central nervous system. Most of the 12q21 deletion syndrome cases reported in the literature involve the SYT1 , PPP1R12A , and CEP290 genes.…”

“…A previous study, published in 2020 by Niclass et al described two candidate genes as critical component of the deletion: SYT1 and PPP1R12A. 11 SYT1 encodes an integral membrane protein of postsynaptic vesicles thought to serve as Ca 2+ sensors in the process of vesicular trafficking and exocytosis. 13 Mutations in the SYT1 cause neurodevelopment disorder described in a rare syndrome, Baker–Gordon syndrome.…”

12q21 Interstitial Deletions: Seven New Syndromic Cases Detected by Array-CGH and Review of the Literature

“…Interstitial deletions in 12q21 have been described in a dozen patients who were all carriers of non-recurrent copy number variants (CNVs) [1][2][3][4][5][6][7][8][9][10]. Despite common features, such as developmental delay and/or intellectual disability (DD/ID), congenital genitourinary, brain malformations and ectodermal anomalies, the clinical presentation is characterized by wide clinical expressivity with severity and signs depending on the size and location of the deletions and on the involved genes.…”

“…A critical region (CR) in 12q21.2 has recently been narrowed down to 1.6 Mb including the four genes Synaptogamin 1 (SYT1, OMIM *185605), PRKC Apoptosis WT1 Regulator (PAWR, OMIM *601936), Protein Phosphatase 1 Regulatory Subunit 12A (PPP1R12A, OMIM *602021) and Otogelin-like protein (OTOGL, OMIM *614925). Of these four, the major candidates seem to be SYT1, encoding a highly conserved synaptic vesicle protein, and PPP1R12A, encoding a regulator of myosin phosphatase acting in neurotransmitter release [5].…”