A genotype and phenotype analysis of SMAD6 mutant patients with radioulnar synostosis

Abstract

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SMAD6-deficiency in human genetic disorders

“…Patients with RUS 9 , 13 (cases, N = 93) (probands, N = 77, Table 1 ) are most frequently characterised by bilateral RUS (69%; isolated ( N = 42/61), familial ( N = 22/32)), followed by unilateral left-sided RUS in sporadic patients ( N = 15/42, 36%) versus right-sided RUS ( N = 4/42, 10%), while no susceptibility for left- or right-sided RUS was observed in families ( N = 5/32, 16%). Affected individuals within a single pedigree can show both bilateral and unilateral RUS.…”

“…Surgical correction is frequently necessary to prevent complications 24 such as developmental delay, facial abnormality, sensory, respiratory and neurological dysfunction, anomalies affecting the eye, and psychological disturbances 25 . Finally, congenital RUS, also referred to as fused forearm bones, is a rare condition with ~500 cases reported in literature 9 , 13 , 26 . This malformation, usually diagnosed before the age of 5 years, is not life-threatening, but corrective surgery and/or medication to control pain might, in some cases, improve the quality of life 13 .…”

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants

“…Approximately 10% of them had a family history with an AD mode of inheritance. In 2019 and a recent study, 7,11 we identified 41.03% RUS pedigrees and 13.99% patients with sporadic RUS harboring SMAD6 variants, approximately 2.63% RUS pedigrees and 0.51% patients with RUS sporadic caused by mutant NOG, and 10.09% patients RUS sporadic caused by chromosome aneuploidy. We still have half of RUS pedigrees and three-quarters of patients with sporadic RUS with unknown genetic cause.…”

“…7,11 The inclusion criteria included diagnosis of RUS (through x-ray imaging) and absence of identifiable syndromes, such as Apert/Crouzon/Pfeiffer syndrome, 12 Holt-Oram syndrome, 13 William syndrome, 14 Ehlers-Danlos Syndrome, 15 and other obvious dysmorphic syndromes. Meanwhile, patients with RUS with mutant SMAD6 or NOG, 7,11 chromosome aneuploidy, 7 or obvious intellectual disability were excluded from this study. We did not encounter any patient with RUSAT in the collection of hundreds of specimens from patients with RUS.…”

“…5,6,9,10 Recently, we have identified that 44 of 436 patients with sporadic RUS were affected by sex chromosome aneuploidy, 16 of 39 (41%) RUS pedigrees and 61 of 436 (14%) patients with sporadic RUS harbored SMAD6 variants, and 1 of 39 (3%) RUS pedigrees and 2 of 436 (0.5%) patients with sporadic RUS harbored NOG variants (unpublished data). 7,11 Nevertheless, a considerable number of patients with RUS have unknown genetic causes.…”