Mendelian inheritance revisited: dominance and recessiveness in medical genetics.

Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.

2020 McKusick Award address.

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

Splenic artery pathology presentation, operative interventions, and outcomes in 88 patients with vascular Ehlers-Danlos syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (VEDS) is rare and associated with arteriopathies. The aim of this study is to investigate the presentation, operative interventions, and outcomes of splenic arterial pathology in a population of more than 1500 individuals with genetically confirmed VEDS due to pathogenic COL3A1 variants. METHODS: Cross-sectional analysis of 1547 individuals was performed. The data were assembled by harmonizing data from three overlapping cohorts with genetically confirmed VEDS: the VEDS Collaborative Natural History Study (N = 242), a single-center cohort (N = 75), and the University of Washington Collagen Diagnostic Lab cohort (N = 1231). Duplicates were identified and removed. Patients were selected for analysis if they had splenic artery aneurysm (SAA), pseudoaneurysm, dissection, thrombosis, or rupture. Demographics, COL3A1 variants, interventions, and outcomes were analyzed. Comparisons by splenic artery rupture were made. RESULTS: A total of 88 patients presented between 1992 and 2021 with splenic artery pathology (5.7% of the cohort; mean age at diagnosis, 37 ± 11.1 years; 50% male). One-third were diagnosed with VEDS prior to the splenic artery pathology diagnosis, and 17% were diagnosed post-mortem. Most had a positive family history (61%). Most had COL3A1 variants associated with minimal normal collagen production (71.6%). Median follow up was 8.5 years (interquartile range, 0.9-14.7 years). Initial presentation was rupture in 47% of the cases. Splenic artery rupture overall was 51% (n = 45), including four cases of splenic rupture. There were no major differences in VEDS-related manifestations or COL3A1 variant type by rupture status. SAA was noted in 39% of the cases. Only 12 patients had splenic artery diameter documented in 12 cases with a median diameter of 12 mm (interquartile range, 10.3-19.3 mm). A total of 34 patients (38.6%) underwent 40 splenic arterial interventions: 21 open surgical, 18 embolization, and one unknown procedure. More than one splenic artery intervention was performed in five cases (14.7%). Open repair complications included arteriovenous fistula (n = 1), intestinal or pancreatic injury (n = 1 each), and four intraoperative deaths. There were no deaths or access site complications related to splenic artery embolization. Four patients (23.5%) developed a new SAA in the remaining splenic artery post embolization. All-cause mortality was 35% (n = 31), including 22 related to a ruptured splenic artery. CONCLUSIONS: Splenic arteriopathy in VEDS is associated with variants that affect the structure and secretion of type III collagen and frequently present with rupture. Rupture and open repair are associated with high morbidity and mortality, whereas embolization is associated with favorable outcomes. Suggest repair considerations at SAA diameter of 15 mm. Long-term follow-up is indicated as secondary splenic arteriopathy can occur.

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor ß gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.

A Targeted Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantification of Peptides from the Carboxyl-terminal Region of Type III Procollagen, Biomarkers of Collagen Turnover.

BACKGROUND: The development of analytical approaches to help reduce the risk of growth hormone (GH) doping is important to fair competition and the health of athletes. However, the reliable detection of GH use remains challenging. The identification of novel biomarkers of GH administration could lead to a better understanding of the physiological response to GH, more sensitive detection of the illicit use of GH in sport, and better management of patients treated for GH disorders. METHODS: We developed a targeted liquid chromatography-tandem mass spectrometry method to simultaneously quantify the carboxyl-terminal propeptide of type III procollagen (P-III-CP) and type III collagen degradation products in human serum. Following proteolysis, we instituted a simple acid precipitation step to reduce digested sample complexity before peptide immunoenrichment, which improved the recovery of one target peptide from serum. We evaluated the concentration of each biomarker at different age ranges and after GH administration in healthy participants. RESULTS: The assay was linear over an estimated concentration range of 0.3 to1.0 nM and 0.1 to 0.4 nM for each surrogate peptide of P-III-CP and collagen fragments, respectively. Intra-day and inter-day coefficients of variation were ≤15%. Biomarker concentrations appeared to vary with age and to reflect age-specific collagen turnover. Moreover, their concentrations changed after GH administration. CONCLUSIONS: Our method quantifies the proteins belonging to the family of P-III-CP and type III collagen degradation products in human serum, which could be used to detect GH administration in athletes and better understand diseases involving GH therapy or altered type III collagen turnover.

Caffey disease is associated with distinct arginine to cysteine substitutions in the proα1(I) chain of type I procollagen.

PURPOSE: Infantile Caffey disease is a rare disorder characterized by acute inflammation with subperiosteal new bone formation, associated with fever, pain, and swelling of the overlying soft tissue. Symptoms arise within the first weeks after birth and spontaneously resolve before the age of two years. Many, but not all, affected individuals carry the heterozygous pathogenic COL1A1 variant (c.3040C>T, p.(Arg1014Cys)). METHODS: We sequenced COL1A1 in 28 families with a suspicion of Caffey disease and performed ultrastructural, immunocytochemical, and biochemical collagen studies on patient skin biopsies. RESULTS: We identified the p.(Arg1014Cys) variant in 23 families and discovered a novel heterozygous pathogenic COL1A1 variant (c.2752C>T, p.(Arg918Cys)) in five. Both arginine to cysteine substitutions are located in the triple helical domain of the proα1(I) procollagen chain. Dermal fibroblasts (one patient with p.(Arg1014Cys) and one with p.(Arg918Cys)) produced molecules with disulfide-linked proα1(I) chains, which were secreted only with p.(Arg1014Cys). No intracellular accumulation of type I procollagen was detected. The dermis revealed mild ultrastructural abnormalities in collagen fibril diameter and packing. CONCLUSION: The discovery of this novel pathogenic variant expands the limited spectrum of arginine to cysteine substitutions in type I procollagen. Furthermore, it confirms allelic heterogeneity in Caffey disease and impacts its molecular confirmation.

Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.

Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy.

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.

Genetic counseling and screening of consanguineous couples and their offspring practice resource: Focused Revision.

There are no evidence-based guidelines to inform genetic counseling for consanguineous couples and their offspring. This focused revision builds on the expert opinions from the original publication of "Genetic Counseling and Screening of Consanguineous Couples and Their Offspring," based on a review of literature published since 2002.

Recessively inherited forms of osteogenesis imperfecta.

More than 90% of people who have osteogenesis imperfecta (OI) have heterozygous mutations in one of the two type I collagen genes, COL1A1 and COL1A2. The effects of these changes range from death in the perinatal period to barely increased fracture frequency and reflect different types of mutations. Introduction of bisphosphonates during the past 20 years has targeted bone fragility by decreased resorption. The recent recognition of biallelic mutations in genes that affect either collagen assembly and processing or the regulation of osteoblast development has raised hopes for therapies that would be specific for single-gene disorders and identify cellular targets in individuals with the dominant forms of OI. These hopes are yet to be met, but the study of the recessively inherited forms of OI has illuminated the details of the collagen processing pathways.

Setting a research agenda for vascular Ehlers-Danlos syndrome using a patient and stakeholder engagement model.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare, syndromic, heritable condition with life-threatening complications that include aortic and arterial aneurysms, dissection, and rupture. This study describes the formation of the vEDS Research Collaborative and methods used for stakeholder engagement. METHODS: The vEDS Research Collaborative was established with an engagement award from the Patient-Centered Outcomes Research Institute to create a framework for a patient-researcher partnership. Between October 1, 2017, and September 30, 2018, the Collaborative used the Patient-Centered Outcomes Research Institute Engagement Rubric to conduct stakeholder engagement to develop a patient-centered research agenda. A modified Delphi technique was used to develop and to refine research topics and questions, gathering input from all stakeholders during three rounds of feedback. RESULTS: Four topic areas were deemed important: mental health and quality of life issues, creating a care team, a holistic approach to vEDS management (medical and surgical), and pregnancy management. An online survey to rank a list of 12 research questions in these topic areas in order of importance was disseminated. The questions were ranked in order of importance through an online survey (N = 197 responses). The survey showed a high degree of alignment in the top priorities among stakeholders. There was a high degree of interest in pragmatic clinical trials evaluating medical management options and health-related quality of life outcomes. CONCLUSIONS: The vEDS Research Collaborative has built a sustainable, coalition model of patient and stakeholder engagement, supported by the vEDS community, to identify a patient-centered, prioritized list of research questions. In articulating a shared vision for the future of vEDS research, the Collaborative has laid the groundwork for developing research protocols aligned with the highest priority questions for the individuals affected by this serious condition that can be translated into future clinical trials.

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a rare but devastating congenital heart defect (CHD) accounting for 25% of all infant deaths due to a CHD. The etiology of HLHS remains elusive, but there is increasing evidence to support a genetic cause for HLHS; in particular, this syndrome is associated with abnormalities in genes involved in cardiac development. Consistent with the involvement of heritable genes in structural heart abnormalities, family members of HLHS patients have a higher incidence of both left- and right-sided valve abnormalities, including bicuspid aortic valve (BAV). CASE PRESENTATION: We previously described (Am J Med Genet A 173:1848-1857, 2017) a 4-generation family with a 6q25.1 microdeletion encompassing TAB2, a gene known to play an important role in outflow tract and cardiac valve formation during embryonic development. Affected adult family members have short stature, dysmorphic facial features, and multiple valve dysplasia, including BAV. This follow-up report includes previously unpublished details of the cardiac phenotype of affected family members. It also describes a baby recently born into this family who was diagnosed prenatally with short long bones, intrauterine growth restriction (IUGR), and HLHS. He was the second family member to have HLHS; the first died several decades ago. Postnatal genetic testing confirmed the baby had inherited the familial TAB2 deletion. CONCLUSIONS: Our findings suggest TAB2 haploinsufficiency is a risk factor for HLHS and expands the phenotypic spectrum of this microdeletion syndrome. Chromosomal single nucleotide polymorphism (SNP) microarray analysis and molecular testing for a TAB2 loss of function variant should be considered for individuals with HLHS, particularly in those with additional non-cardiac findings such as IUGR, short stature, and/or dysmorphic facial features.

Assessment of the Information Sources and Interest in Research Collaboration Among Individuals with Vascular Ehlers-Danlos Syndrome.

BACKGROUND: Patient-centered research requires active engagement of patients. The vascular Ehlers-Danlos Syndrome (vEDS) research collaborative was established to ascertain patient-centered vEDS research priorities and to engage affected individuals as research partners. Evaluation of access to information and interest in research among individuals with vEDS was the first step undertaken as part of this work. METHODS: A 28-question survey was created to evaluate 4 domains of interest: diagnostic and clinical care history, vEDS experience, information resources, and willingness to collaborate with researchers. The survey was created in REDCap™ and disseminated between January and April 2018 via the vEDS social media pages, blogs, and advocacy Web sites. Results were collated and described. A single open-ended question yielded additional narrative data, which were analyzed qualitatively. RESULTS: Of the 300 responses, 228 (76%) were completed on behalf of oneself. The vEDS diagnosis was confirmed by genetic testing for 85% of respondents. When asked "Did a physician explain vEDS to you and how to manage it?" 25% answered no. Most had a primary care provider (65%), cardiologist (56%), and vascular surgeon (52%). Only 32% had a local vascular surgeon. The most commonly reported frustration was no cure/treatment available and the emergency rooms do not know what VEDS is (64.5% and 61.8%, respectively). The Internet was the most useful information source (62.3%) followed by a geneticist (18.4%). Most (87.7%) are willing to share their medical records for research studies (87.7%) and wished to be contacted about future studies (83.8%); however, only 65.4% would be willing to upload medical records via a secure confidential Web application. The most common reason for interest in research partnership was to advance research for a treatment/cure (83.8%) and helping others learn from their experiences (82.9%). The qualitative analysis provided additional insights into the patient experience living with vEDS. CONCLUSIONS: Among individuals with vEDS, there is substantial frustration with the lack of treatment, lack of knowledge among health care providers, and a high degree of interest in research involvement. The survey highlights an opportunity to discuss the optimal modality for research participation and methodologies for building trust in the research teams. The methodology lessons learned can also be applied to other rare vascular diseases.

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

Trends over 42 years in the Adult Medical Genetics Clinic at the University of Washington.

PURPOSE: We analyzed the patients served by the University of Washington Adult Genetic Medicine Clinic (UWAGMC) over a 42-year period to determine how clinical services have changed and to evaluate the contributing factors. METHODS: We conducted a retrospective survey of patients seen by UWAGMC that included patients seen from 1975 to 2016. Variables considered included referral indication, disease status, and clinic visit date. Indications for referral were then binned into clinical categories for descriptive analysis. RESULTS: Of 30,780 patient visits during the 39 years for which data were available, 57.3% occurred in the last decade. Referrals for breast/ovarian cancer or colon/endometrial cancer account for 74.8% of cancer referrals since 1998. Huntington disease patients made up 46% of neurological referral indications. Telephone screening implemented in 2013 has reduced the number of referrals for hypermobile Ehlers-Danlos syndrome. CONCLUSION: Referral indications increased with clinical testing availability and because of the academic programs of UWAGMC providers. With increased public awareness of heritable conditions, prescreening self-referrals were used to allocate limited resources. These trends demonstrate the need for more geneticists in adult medicine to expand centers of excellence for rare diseases and to serve the increasing numbers of adult patients with genetic conditions.

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.

Mobility in osteogenesis imperfecta: a multicenter North American study.

PURPOSE: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes. METHODS: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics. RESULTS: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV). CONCLUSION: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.