IllnessClefting, non-syndromal; differential diagnosis

NGS +

Orofacial clefts are the most common orofacial malformations in humans. During the first 6-10 weeks of gestation, the bones and skin of the fetal upper jaw, nose, and mouth fuse together normally to form the roof of the mouth and upper lip. Cleft formations occur when parts of the lip and/or palate do not completely fuse together. The reasons for most clefts remain unclear; some may be related to genetics, others to environmental factors (medications and chemicals during pregnancy, deficiencies in key prenatal nutrients, smoking and alcohol etc.). An increased risk of recurrence of clefts in relatives suggests a high degree of heritability. Monogenic causes, however, are the exception; they include mutations in genes encoding cell proliferation and migration, cell-cell adhesion proteins, folate and homocysteine metabolism. In essence, orofacial clefts are considered typically complex and multifactorial disorders caused by multiple genetic and environmental factors. In contrast to various cleft formation syndromes, the molecular genetic yield of non-syndromic clefts in familial cases hardly exceeds 10%. Therefore, syndromic cleft genes should be included in the differential diagnosis. Nevertheless, the clinical diagnosis clefting is rarely accompanied by positive DNA test results. +

Reference: https://www.frontiersin.org/articles/10.3389/fcell.2020.592271/full

https://richtlijnendatabase.nl/richtlijn/behandeling_van_patienten_met_een_schisis/diagnostic_genetic_testing_in_isolated_clefts_of_the_lip_alveolus_and_or_palate.html

• Acampomelic campomelic dysplasia (SOX9)
• Allelic: Abruzzo-Erickson syndrome (TBX22)
• Allelic: Ectodermal dysplasia 3, Witkop type (MSX1)
• Allelic: Joubert syndrome 10 (OFD1)
• Allelic: Simpson-Golabi-Behmel syndrome, type 2 (OFD1)
• Bamforth-Lazarus syndrome (FOXE1)
• Blepharocheilodontic syndrome 1 (CDH1)
• Campomelic dysplasia (SOX9)
• Cerebellar ataxia, neuropathy + vestibular areflexia syndrome (RFC1)
• Cleft palate with ankyloglossia (TBX22)
• Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (MTHFD1)
• Craniofrontonasal dysplasia (EFNB1)
• Cystathioninuria (CTH)
• Dimethylglycine dehydrogenase deficiency (DMGDH)
• Folate malabsorption, hereditary (SLC46A1)
• Frontometaphyseal dysplasia 1 (FLNA)
• Gastric cancer, hereditary diffuse, with/-out cleft lip and/or palate (CDH1)
• Glutamate formiminotransferase deficiency (FTCD)
• Glycine N-methyltransferase deficiency (GNMT)
• Homocystinuria due to MTHFR deficiency (MTHFR)
• Homocystinuria, B6-responsive and nonresponsive types (CBS)
• Homocystinuria-megaloblastic anemia, cbl E type (MTRR)
• Homocystinuria-megaloblastic anemia, cblG complementation type (MTR)
• Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (AHCY)
• Jackson-Weiss syndrome (FGFR1, FGFR2)
• Loeys-Dietz syndrome 4 (TGB2)
• Marshall syndrome (COL11A1)
• Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFR)
• Megaloblastic anemia, folate-responsive (SLC19A1)
• Melnick-Needles syndrome (FLNA)
• Mental retardation syndrome, XL, Siderius type (PHF8)
• Mental retardation, XL, Snyder-Robinson type (SMS)
• Methionine adenosyltransferase deficiency, AR (MAT1A)
• Microphthalmia, syndromic 2 (BCOR)
• Myopathy, congenital, progressive, with scoliosis (PAX7)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodevelopmental disorder with cardiomyopathy, spasticity + brain abnormalities (SHMT2)
• Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (MTHFS)
• Orofacial cleft 10 (SUMO1)
• Orofacial cleft 5 (MSX1)
• Orofacial cleft 6 (IRF6)
• Orofaciodigital syndrome I (OFD1)
• Otopalatodigital syndrome, type I + II (FLNA)
• Otospondylomegaepiphyseal dysplasia, AD (COL11A2)
• Otospondylomegaepiphyseal dysplasia, AR (COL11A2)
• Renpenning syndrome (PQBP1)
• Stickler syndrome, type I (COL2A1)
• Stickler syndrome, type II (COL11A1)
• Tooth agenesis, selective, 1, with/-out orofacial cleft (MSX1)
• Transcobalamin II deficiency (TCN2)
• Treacher Collins syndrome 1 (TCOF1)
• Van der Woude syndrome (IRF6)
• Van der Woude syndrome 2 (GRHL3)