Aortic Dissection and a Previously Unreported ACTA2 Missense Variant Mutation in a Young Patient: A Case Report.

Hereditary connective tissue disease is known to cause aortic lesions at an early age. Familial aortic aneurysm/dissection is caused due to an ACTA2 mutation that affects smooth muscle structure. We present a case of a 15-year-old boy with a mild developmental disorder in whom no abnormalities were identified on previous physical examinations. The patient presented with severe left heart failure, extensive dissection from the ascending aorta to the common iliac artery, and myocardial and cerebral infarctions. He underwent an urgent Bentall surgery. Six months later, the patient underwent surgical reconstruction of the abdominal aorta from the aortic arch and returned to normal daily activities. Pathological examination demonstrated the absence of elastic fibers but presence of abundant reticular fibers and mucopolysaccharides from the tunica intima to the media. Genetic testing revealed a heterozygous missense variant of the ACTA2 gene. To the best of our knowledge, this is the first sporadic case of structurally abnormal smooth muscle organization resulting in clinical symptoms with no previously reported pathogenicity.

AMPD2 plays important roles in regulating hepatic glucose and lipid metabolism.

Dysregulation of hepatic glucose and lipid metabolism can instigate the onset of various metabolic disorders including obesity, dyslipidemia, insulin resistance, type 2 diabetes, and fatty liver disease. Adenosine monophosphate (AMP) deaminase (AMPD), which converts AMP to inosine monophosphate, plays a key role in maintaining adenylate energy charge. AMPD2 is the major isoform present in the liver. However, the mechanistic link between AMPD2 and hepatic glucose and lipid metabolism remains elusive. In this study, we probed into the hepatic glucose and lipid metabolism in AMPD2-deficient (A2-/-) mice. These mice exhibited reduced body weight, fat accumulation, and blood glucose levels, coupled with enhanced insulin sensitivity while maintaining consistent calorie intake and spontaneous motor activity compared with wild type mice. Furthermore, A2-/- mice showed mitigated obesity and hyper-insulinemia induced by high-fat diet (HFD) but elevated levels of the serum triglyceride and cholesterol. The hepatic mRNA levels of several fatty acid and cholesterol metabolism-related genes were altered in A2-/- mice. RNA sequencing unveiled multiple alterations in lipid metabolic pathways due to AMPD2 deficiency. These mice were also more susceptible to fasting or HFD-induced hepatic lipid accumulation. The liver exhibited elevated AMP levels but unaltered AMP/ATP ratio. In addition, AMPD2 deficiency is not associated with the adenosine production. In summary, this study established a link between purine metabolism and hepatic glucose and lipid metabolism via AMPD2, providing novel insights into these metabolic pathways.

Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays. Four variants with amino acid replacement in the motifs essential for the intracellular kinase function lost SMAD-dependent signaling. Most of other variations in the kinase domain also caused marked downregulation of signaling; however, two variants behaved as the wild-type ACVRL1 did, while computational classifiers predicted their functional abnormalities. Three-dimensional structure prediction using the ColabFold program supported the significance of the L45 loop and NANDOR domain of ACVRL1 for its association with SMAD1 and BMPR2, respectively, and the variations in these motifs resulted in the reduction of SMAD signaling. On the other hand, two of the GS domain variants maintained high signal transduction capacity, which did not accord with their computational pathogenicity prediction. These results affirm the requirement of a combinatory approach using computational and experimental analyses to accurately predict the pathogenicity of ACVRL1 missense variants in the HHT patients.

Genetic association analysis of 77,539 genomes reveals rare disease etiologies.

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-ß regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.

Case Report: Spontaneous Postpartum Quadruple Cervicocephalic Arterial Dissection With a Heterozygous COL5A1 Variant of Unknown Significance.

Pregnancy-associated cervicocephalic arterial dissection is rare, and its pathophysiology remains poorly understood. Despite the hypothesized contribution to pathogenesis, connective tissue diseases and genetic factors are rarely identified in clinical cases. We describe a case of postpartum arterial dissection involving all four cervicocephalic arteries resulting in acute cerebral infarction. The patient underwent successful endovascular thrombectomy and angioplasty and recovered fully without sequelae. Genetic screening for connective tissue diseases identified a heterozygous missense COL5A1 variant with unknown clinical significance. Two genetically related family members later developed arterial abnormalities, and one of them tested positive for the same COL5A1 gene variant as our patient, while the other was scheduled for genetic testing. The extensive clinical presentation of our patient and the prevalence of arterial abnormalities in her family warrant further assessment of the association between the identified COL5A1 gene variant and the pathogenesis of arterial dissections.

Long-term durability of a reimplantation valve-sparing aortic root replacement can be expected in both Marfan syndrome and Loeys-Dietz syndrome.

OBJECTIVES: The goal of this study was to evaluate the surgical outcomes of a valve-sparing root replacement using the reimplantation technique for annuloaortic ectasia in patients with Marfan syndrome (MFS) and in those with Loeys-Dietz syndrome (LDS). METHODS: We reviewed 103 patients with MSF with mutations in the fibrillin-1 gene and 28 patients with LDS with mutations in the transforming growth factor-beta receptor and 2, SMAD3 and transforming growth factor beta-2 from 1988 to 2020. RESULTS: Forty-four (42.7%) patients with MFS [26 men, 31 (7.6) years] and 10 (35.7%) patients with Loeys-Dietz syndrome (LDS) [7 men, 22 (standard deviation: 8.6) years] who had no aortic dissection and underwent valve-sparing root replacement were included. The preoperative sinus diameter [46 (45-50.5) mm in those with MFS vs 48 (47-50) mm in those with LDS, p = 0.420] and the percentage of aortic insufficiency > grade 2+ [31.8% (10/44) in patients with MFS vs 10.0% (1/10) in those with LDS, p = 0.667] revealed no significant differences between the 2 groups. The cumulative incidences of aortic insufficiency greater than grade 1 (p = 0.588) and aortic valve reoperation (p = 0.310) were comparable between the 2 groups. Patients with LDS had a higher tendency towards aortic dissection after the initial operation (p = 0.061) and a significantly higher cumulative incidence of aortic reoperation (p = 0.003) versus those with MFS. CONCLUSIONS: Patients with MFS and those with LDS showed similar cumulative incidences of recurrent aortic valve insufficiency and aortic valve reoperation. Those with LDS revealed a higher cumulative incidence of aortic reoperation and a greater tendency towards aortic dissection after the initial operation compared with those with MFS.

The differences in surgical long-term outcomes between Marfan syndrome and Loeys-Dietz syndrome.

OBJECTIVE: The aim of this study was to disclose the differences of surgical outcomes between Marfan syndrome with mutations in fibrillin-1 gene and Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2. METHODS: We reviewed 368 patients aged less than 50 years who underwent surgery for thoracic aortic diseases between 1988 and 2019, and enrolled 99 patients with Marfan syndrome (26.9%; 57 men, 33 ± 7.5 years) and 24 patients with Loeys-Dietz syndrome (6.5%; 13 men, 28 ± 11 years). RESULTS: Freedom from all causes of mortality was similar between the 2 groups (P = .40, log-rank). The cumulative incidence of reintervention was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P = .016, Gray). The cumulative incidence of first aortic arch reoperation for aortic arch aneurysm was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P < .001, Gray). The cumulative incidence of first aortic root reoperation for aortic root aneurysm (P = .57, Gray) and first descending aorta reoperation for descending aortic aneurysm (P = .76, Gray) was similar between the 2 groups. The cumulative incidence of aortic dissection after initial surgery was significantly lower in Marfan syndrome than in Loeys-Dietz syndrome (P = .0059, Gray). CONCLUSIONS: Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2 revealed higher rates of reoperation, and more specifically the arch reoperation was higher in those with Loeys-Dietz syndrome than those with Marfan syndrome. Aggressive arch surgery in the initial operation on the proximal aorta is recommendable in Loeys-Dietz syndrome to avoid additional aortic events. In Marfan syndrome, this is controversial in patients without dissection because of a low possibility to expand.

Nonsurgical treatment of cerebral ischemia associated with ACTA2 cerebral arteriopathy: a case report and literature review.

Mutations in ACTA2 gene can lead to multisystemic smooth muscle dysfunction, including cerebrovascular disease. Treatment strategies for this rare entity remain controversial, and patients are at increasing risk of neurological sequelae. We herein present the case of an 11-year-old boy previously diagnosed with an ACTA2 gene mutation who developed repetitive transient ischemic attacks and treated with bosentan, an oral endothelin receptor antagonist. Magnetic resonance imaging revealed bilateral, periventricular white matter T2 hyperintensities, and magnetic resonance angiography identified several abnormalities including fusiform dilatation in the proximal segments of internal cerebral arteries, together with followed by terminal segmental stenosis. The distal branches showed a markedly straightened course with no increase in lenticulostriate collaterals. Magnetic resonance imaging also revealed an increase in the number and size of large periventricular white matter lesions located in the left frontal lobe with the progression of ischemic symptoms. Instead of revascularization surgery, the administration of bosentan was started due to the high risk of perioperative ischemic sequelae. After bosentan initiation, the patient's repetitive episodes of cerebral ischemia ceased, and there has been no increase in the number of white matter lesions for 7 years. Bosentan might be beneficial for treating cerebral ischemia associated with ACTA2 cerebral arteriopathy by maintaining the dilatation of stenotic vessels and adequate systemic blood flow and should be considered before performing revascularization surgery.

Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14).

BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. METHODS: Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon-intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. RESULTS: In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5-10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8-10 tended to be shared by multiple (2-7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. CONCLUSIONS: In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Impact of Annual Cardiovascular Screening Tests in Patients with Type 2 Diabetes Mellitus without Previous Histories of Cardiovascular Disease: Four-year Clinical Outcomes.

Objective We previously reported that, among asymptomatic patients with type 2 diabetes mellitus (T2DM) without a history of cardiovascular disease (CVD), up to 19% of the patients with myocardial ischemia were detected by annual cardiovascular screening tests (ACVSTs). Thus, the present study assessed the long-term clinical outcomes of ACVSTs in those patients. Methods Six hundred and fifty-seven outpatients with T2DM who received ACVSTs at least once or not at all from April 2014 to March 2018 were defined as the S and NS groups, respectively. The data were compared between these two groups. Results This study revealed that, among outpatients with T2DM in our hospital over those four years, with the increasing frequency of receiving ACVSTs, 1) the frequency of the internal use of statins, anti-platelets, and renin-angiotensin system inhibitors, which are well-known as medications for preventing CVD, significantly increased; 2) low-density lipoprotein-cholesterol and triglyceride levels significantly improved; 3) levels of highly sensitive C-protein, a strong predictors of CVD, were significantly suppressed; 4) the progression of renal dysfunction was significantly suppressed; 5) the cumulative of four-point major adverse cardiovascular events and admissions due to heart failure significantly decreased; and 6) the cumulative of all-cause mortality was significantly suppressed. Conclusions Given the above, it may be important to continue ACVSTs in outpatients with T2DM without a history of CVD for several years.

Aortic dissection during pregnancy and puerperium: A Japanese nationwide survey.

AIM: This study aimed to characterize the incidence and clinical significance of pregnancy-related aortic dissection using a large-scale survey in Japan. METHODS: A questionnaire requesting the detailed information included in the clinical charts of pregnancy-related aortic dissection cases (without any personally identifying information) was designed between 2013 and 2017 and administered to 407 perinatal centers in Japan. The response rate was 70.5%. Seventeen cases of pregnancy-related aortic dissection were identified. RESULTS: Maternal death due to aortic dissection was observed in nine patients (56.2%) while seven survived (43.8%). Dissection occurred during the postpartum period in 10 cases (62.5%), the third trimester in 4 (25.0%), labor in 1 (6.2%), and the second trimester in 1 (6.2%). The most common underlying diseases were: Marfan syndrome (25.0%), Loeys-Dietz syndrome (6.2%), hypertension (6.2%), and Takayasu aortitis (6.2%). Stanford type A aortic dissection was associated with maternal death during both pregnancy and the postpartum period. However, deceased patients showed lower rates of pre-diagnosed connective tissue disease than did survivors. CONCLUSIONS: The mortality rate of aortic dissection that occurred during pregnancy or postnatal periods was more than 50%. Aortic dissection occurred more frequently in the postnatal period than during pregnancy, and less frequently in women previously diagnosed with connective tissue disease than in women without any medical history of aortic disorders. If symptoms suggestive of aortic dissection, such as severe back pain, are observed, even after the end of pregnancy, exhaustive diagnostic examinations should be carried out.

Surgical Outcome and Histological Differences between Individuals with TGFBR1 and TGFBR2 Mutations in Loeys-Dietz Syndrome.

PURPOSE: To identify differences in surgical outcomes between patients with transforming growth factor-beta receptor (TGFBR) 1 and TGFBR2 mutations in Loeys-Dietz syndrome (LDS). METHODS: In all, 22 LDS patients between 1998 and 2015 were divided into the two groups: TGFBR1 (n = 11) and TGFBR2 mutation (n = 11). RESULTS: The freedom from aortic reoperation was similar between the two groups (p = 0.19, log-rank). In the subanalysis, the freedom from aortic reoperation was lower in female patients with TGFBR2 mutations (n = 6) than in other patients (p = 0.08). The freedom from aortic dissection (AD) after the initial surgery was also lower in female patients with TGFBR2 mutation than in other patients (p = 0.025). All patients with TGFBR2 mutations revealed grade III cystic medial necrosis (CMN), whereas 67% of patients with TGFBR1 mutations showed CMN (p = 0.033) and only one patient had grade III (p <0.001). CONCLUSION: LDS patients with TGFBR2 mutations had higher grade of CMN than those of TGFBR1 mutations. In particular, in female patients with TGFBR2 mutations, AD after the initial surgery and reoperation were more frequent than those of other LDS patients.

Association of protein tyrosine phosphatase 1B gene polymorphism with the effects of weight reduction therapy on bodyweight and glycolipid profiles in obese patients.

AIMS/INTRODUCTION: Weight reduction therapy is the primary treatment to prevent complications of obesity, such as lifestyle diseases and cardiovascular disease; however, to date, useful methods and genetic factors for predicting the outcomes of weight reduction therapy in obese patients have not been established. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator for insulin and leptin signaling, potentially modulates glucose and energy homeostasis. This study aimed to investigate the contribution of PTPN1 polymorphisms on weight reduction and diabetes in obese Japanese patients. MATERIALS AND METHODS: PTPN1-tagged single-nucleotide polymorphisms (SNPs) rs3787348 and rs6067484 were genotyped in 447 obese Japanese patients from the general population. In this prospective cohort study, all obese patients underwent a 3-month weight reduction therapy with lifestyle modifications, as recommended by guidelines. RESULTS: In obese patients (male/female 196/251, age 50 ± 15 years, body mass index [BMI] 32 ± 6 kg/m2 ), the minor allele appeared at a frequency of 45.5% in rs3787348 SNP of the PTPN1 gene. The T allele of rs3787348 was significantly associated with a higher BMI (P = 0.041 in the additive model). The patients with the T allele in SNP rs3787348 of PTPN1 had significantly smaller reductions in BMI, bodyweight and waist circumference levels during weight reduction therapy (BMI G/G, -1.9 ± 0.2; G/T, -1.5 ± 0.1; T/T, -1.2 ± 0.1; P = 0.001 in the additive model). CONCLUSIONS: Our findings show that the SNP rs3787348 in PTPN1 was associated with the effects of weight reduction therapy on BMI and waist circumference among obese Japanese patients.

Histologic differences between the ascending and descending aortas in young adults with fibrillin-1 mutations.

OBJECTIVES: This study aimed to review the clinical results of young adult patients with aortic disease associated with mutations in the fibrillin-1 gene (FBN1) and disclose the histologic differences between the ascending and descending aortas. METHODS: Between 2012 and 2015, 94 patients aged less than 50 years underwent surgery for thoracic aortic diseases. Forty-two patients (44.7%) had FBN-1 mutations. Of these, 40 patients (42.5%) with surgical specimens for histologic evaluation were included in the study. With the histologic results including the specimen sampled at their previous operations, cystic medial necrosis was classified into 3 grades according to the degree of the cystic area. RESULTS: Thirty-nine patients (97.5%) had aortic root dilatation (Z ≥2), and 13 patients (32.5%) had ectopia lentis. Thirty-nine patients (97.5%) fulfilled the diagnostic criteria for Marfan syndrome. There were no in-hospital deaths. The majority (27/29: 93.1%) of the specimens of the ascending aorta revealed cystic medial necrosis pattern. With grade III being the most severe condition, these cases were classified into grade I (n = 2), grade II (n = 5), and grade III (n = 20). In contrast, only 6 specimens (6/17: 35.3%) of the descending aorta showed a cystic medial necrosis pattern that was classified into grade I (n = 2) and grade III (n = 4), (P < .00001). CONCLUSIONS: Fewer specimens of the descending aorta revealed cystic medial necrosis compared with those of the ascending aorta. This difference might influence the characteristic aortic disease in Marfan syndrome associated with FBN-1 mutations.

Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an ACVRL1 Mutation.

Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.

A Nonsense SMAD3 Mutation in a Girl with Familial Thoracic Aortic Aneurysm and Dissection without Joint Abnormality.

INTRODUCTION: Thoracic aortic aneurysms and dissections (TAAD) are rare in children and often associated with underlying genetic disorders accompanied with other systemic manifestations, including connective or osteo-articular tissue diseases. CASE PRESENTATION: We report the case of a 10-year-old girl with a novel nonsense SMAD3 mutation, p.Glu102X, who presented with familial TAAD without any signs of osteoarthritis. Histological analysis of aorta fragments from the patient with TAAD obtained during surgery revealed elastin degradation and inflammatory infiltration of T cells with dense CD31 + microvessels, which is consistent with previous findings. Interestingly, the family members with the SMAD3 mutation developed IgA nephropathy. CONCLUSION: Because the TGF-ß/Smad signalling pathway plays an important role in the primary pathogenesis of IgA nephropathy and TAAD, we presume that IgA nephropathy could be a novel clinical phenotype of SMAD3 deficiency. Further accumulation of genetically proven cases with SMAD3 deficiency is needed to more accurately characterize phenotypic variability and elucidate a wide spectrum of TGF-ß-associated disorders.