SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.

Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.

Designing a plan to find treatments for epilepsies linked to the CACNA1A gene and test them in clinical trials for FDA approval CACNA1A-related disorders are rare conditions that affect brain development and are caused by changes in the CACNA1A gene. This gene provides instructions for making a protein called Cav2.1, which plays a crucial role in fast communication between nerve cells. The disorders can lead to various neurological problems such as seizures, epilepsy, developmental delays, intellectual disability, and autism. The severity of these disorders varies, and individuals may experience a broad range of seizures. More than 1700 different genetic changes in the CACNA1A gene have been identified, with over 400 considered likely to cause the disorders. However, there is limited information on the clinical and molecular aspects of these changes. Despite the significant impact on individuals' lives, there are currently no definitive treatments for CACNA1A-related epilepsies. To address this gap, the CACNA1A Foundation was established in March 2020. The Foundation aims to improve the lives of individuals with CACNA1A-related disorders, including epilepsy. It has developed a comprehensive set of tools, including patient-derived cells and new disease models, to advance research. Additionally, the Foundation has initiated initiatives to prepare for clinical trials and has formed a global CACNA1A Research Network with over 60 scientists and clinicians collaborating to develop specific treatments and, ultimately, find a cure.

Behavioral Phenotypes and Comorbidity in 3q29 Deletion Syndrome: Results from the 3q29 Registry.

3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric disorders. However, the full spectrum of behavioral phenotypes associated with 3q29del is still evolving. Individuals with 3q29del (n = 96, 60.42% male) or their guardian completed the Achenbach Child or Adult Behavior Checklist (CBCL/ABCL) via the online 3q29 registry (3q29deletion.org). Typically developing controls (n = 57, 49.12% male) were ascertained as a comparison group. We analyzed mean performance on the CBCL/ABCL for individuals with 3q29del and controls across composite, DSM-keyed, and developmental scales; and the relationship between CBCL/ABCL performance and clinical and developmental phenotypes for individuals with 3q29del. Individuals with 3q29del showed significantly elevated behavioral and developmental impairment relative to controls across CBCL/ABCL domains. A substantial proportion of study participants with 3q29del scored in the Borderline or Clinical range for composite and DSM-keyed scales, indicating significant behavioral problems that may require clinical evaluation. We found that the preschool CBCL DSM-keyed autism spectrum problems scale is a potential screening tool for autism spectrum disorder (ASD) for individuals with 3q29del; CBCL/ABCL DSM-keyed scales were not accurate screeners for anxiety disorders or attention-deficit/hyperactivity disorder (ADHD) in our study sample. We identified a high degree of psychiatric comorbidity in individuals with 3q29del, with 60.42% (n = 58) of individuals with 3q29del scoring in the Borderline or Clinical range on two or more DSM-keyed CBCL/ABCL scales. Finally, we found that the degree of developmental delay in participants with 3q29del does not explain the increased behavioral problems observed on the CBCL/ABCL. The CBCL/ABCL can be used as screening tools in populations such as 3q29del, even in the presence of substantial psychiatric comorbidity. These results expand our understanding of the phenotypic spectrum of 3q29del and demonstrate an effective method for recruiting and phenotyping a large sample of individuals with a rare genetic disorder.

A shock to the (health) system: experiences of adults with rare disorders during the first COVID-19 wave.

BACKGROUND: Before COVID-19, people with rare diseases (RD) experienced numerous disparities in quality of life and healthcare access and quality, yet little is known about the experiences of this underserved group during the pandemic. RESULTS: During the first wave of the COVID-19 pandemic in the United States, spring and summer of 2020, 759 participants representing 231 unique RDs responded to open-ended questions about the impact of the pandemic on life with a RD, healthcare access, and coping. Qualitative conventional content analysis was used to analyze responses. Identified themes represented positive and negative dimensions of change, including a shock to the (health) system, coping with uncertainty, and the value of social support while isolated. CONCLUSIONS: Limitations in healthcare access and quality were the most frequently described as impacts of COVID-19. Other major negative impacts included exacerbation of symptoms, psychological distress, and a lack of usual social support and reliable information. However, participants also noted silver linings, especially in healthcare. For some, expanded telehealth enhanced their ability to access medical and mental health providers and RD specialists. Finally, many participants hoped that, by highlighting social and health inequities faced by people with RDs and other minorities, the pandemic would prompt greater understanding and policies that could improve the quality of life of the RD community.

Novel SYNGAP1 Variant in an Adult Individual Affected by Intellectual Disability and Epilepsy: A Cold Case Solved through Whole-Exome Sequencing.

Introduction: Nowadays, whole-exome sequencing (WES) analysis is an essential part in the diagnostic pathway of individuals with complex phenotypes when routine exams, such as array-CGH and gene panels, have proved inconclusive. However, data on the diagnostic rate of WES analysis in adult individuals, negative to first-tier tests, are lacking. This is because initiatives with the aim of diagnosing rare diseases focus mainly on pediatric unsolved cases. Case Presentation: We hereby present a 45-year-old woman with severe intellectual disability, previous psychomotor developmental delay, behavioral disorders, stereotypies, nonconvulsive epilepsy, and dysmorphisms. The proband first came to our attention when she was 4 years old (in 1982); since then, she has undergone several clinical and instrumental assessments, without reaching a genetic diagnosis. At last, through WES analysis, a novel de novo variant in SYNGAP1 was found. The clinical characteristics associated with SYNGAP1 are similar to those presented by the proband. Conclusion: The variant is predicted to be deleterious and is most probably the cause of the proband's phenotype. The perseverance of the clinicians and the family allowed us to reach a diagnosis in a woman with a more than 30-year history of clinical evaluations, instrumental assessments, and genetic tests. This diagnosis was of significant relevance in genetic counseling for family members and the proband herself.

Total Hip Arthroplasty in Patients Who Have Marfan Syndrome: Adverse Events and 5-Year Revision Rates.

BACKGROUND: Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. METHODS: Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. RESULTS: Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. CONCLUSIONS: Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.

Study protocol of the HD-MED study aiming to personalize drug treatment in Huntington's disease: a longitudinal, observational study to assess medication use and efficacy in relation to pharmacogenetics.

Background: Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Currently, HD can only be managed symptomatically, including a large variety of prescribed drugs. Many HD patients experience negative medication effects (e.g. side effects or non-response). Pharmacogenetic (PGx) studies show how genetic variation affects both medication efficacy and toxicity and holds the potential to improve these outcomes of drug treatment. Primary objective: To classify the effect of the PGx profile of CYP2C19 and CYP2D6 in HD gene expansion carriers on negative medication effects of HD-related medication. Design: Multicenter, observational study with 1-year follow-up. Adult HD gene expansion carriers who use one or more HD-related medications are eligible to participate. Methods and analysis: A detailed overview of medication use, medication efficacy, and side effects is retrospectively and prospectively collected via medication diaries, questionnaires, phone calls, and pharmacy medication verification schemes. PGx analysis on whole blood-extracted DNA is performed with Agena Bioscience VeriDose® Core Panel and long-range polymerase chain reaction copy number variation analysis. Per the study protocol-defined negative medication effects in HD gene expansion carriers with a genotype predicted poor or ultrarapid metabolizer phenotype will be compared with HD gene expansion carriers with a predicted intermediate and normal metabolizer phenotype. Frequencies will be analyzed via χ2 and logistic multivariate regression analysis. In addition, we summarize in this manuscript HD-relevant PGx prescription recommendations to improve drug therapy. Ethics: The original study protocol was approved by the medical research ethics committee Leiden Den Haag Delft on 26 November 2019. Discussion: HD-MED is a low-risk study that will generate personalized PGx results that can immediately be implemented in clinical practice, thus potentially improving pharmacovigilance and patients' quality of life. Registration: This study is registered in the International Clinical Trial Registry Platform under registration number NL8251, URL https://trialsearch.who.int/Trial2.aspx?TrialID=NL8251.

Self-reported symptoms of everyday executive dysfunction, daytime sleepiness, and fatigue and health status among adults with congenital aniridia: a descriptive study.

Background: Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group. Methods: Twenty-nine adults (aged 18-79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function-Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L). Results: Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants. Conclusions: The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients.

Kidney Biopsy Un-masquerading Plasma Cell Leukemia Diagnosed as Acute Myeloid Leukemia: An Unusual Clinical Experience.

Plasma cell leukemia (PCL) is a rare aggressive variant of plasma cell myeloma. The differential diagnosis of PCL includes multiple myeloma (MM), other leukemias, and lymphomas with abnormal cells circulating in the peripheral blood. In addition, infectious or autoimmune diseases can cause reactive polyclonal plasmacytosis, which could confuse us with PCL occasionally. Sometimes, blastoid morphology can cause confusion in diagnosis, and immunohistochemistry is needed to differentiate PCL from other forms of leukemias and lymphomas. Here, we present a rare case of PCL diagnosed as acute myeloid leukemia (AML) with kidney biopsy establishing the correct diagnosis.

Nummular headache: a case report of remission following ketogenic diet and botulinum toxin type A injections.

Nummular headache is an unusual facial pain disorder with no evidence-based therapy recommendations. The ketogenic diet is an alternative therapy that demonstrated to be effective in migraineurs, but it was never used in the setting of nummular headache. We describe a 58-years old female patient with nummular headache successfully treated with a 6-months ketogenic diet and botulinum toxin type A injections. Ketogenic diet could be an effective alternative/complementary therapy in nummular headache patients although more studies are needed to confirm our results.

Biochemical and cellular effects of a novel missense mutation of the AGXT gene associated with Primary Hyperoxaluria Type 1.

Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal disease caused by mutations in AGXT that lead to the deficiency of alanine:glyoxylate aminotransferase (AGT). AGT is a liver pyridoxal 5'-phosphate (PLP)-dependent enzyme that detoxifies glyoxylate inside peroxisomes. The lack of AGT activity results in a build-up of glyoxylate that is oxidized to oxalate, then culminating in hyperoxaluria often leading to kidney failure. Most pathogenic mutations reduce AGT specific activity because of catalytic defects, improper folding, mistargeting to mitochondria, reduced intracellular stability, dimerization, and/or aggregation. Administration of pyridoxine (PN), a precursor of PLP, is a therapeutic option available for PH1 patients carrying responsive genotypes through the ability of the coenzyme to behave as a chaperone. Here, we report the clinical and biochemical characterization of the novel mutation c.1093G > T (p.Gly365Cys) identified in a Japanese patient. In silico studies predict that the p.Gly365Cys mutation causes a steric clash resulting in a local rearrangement of the region surrounding the active site, thus possibly affecting PLP binding and catalysis. Indeed, the purified p.Gly365Cys mutant displays proper folding but shows an extensive decrease of catalytic efficiency due to an altered PLP-binding. When expressed in AGXT1-KO HepG2 cells the variant shows reduced specific activity and protein levels in comparison with wild type AGT that cannot be rescued by PN treatment. Overall, our data indicate that the mutation of Gly365 induces a conformational change at the AGT active site translating into a functional and structural defect and allow to predict that the patients will not be responsive to vitamin B6, thus supporting the usefulness of preclinical studies to guide therapeutic decisions in the era of precision medicine.

Case study using RWD in the context of a pivotal trial for regulatory approval in a rare disease.

Rare disorders impact millions of children worldwide, and developing new medicines in this setting is associated with multiple challenges. In this paper, we share a successful story of how real-world data (RWD) were leveraged to accelerate evidence generation and patient access to a life-changing therapy in patients with severe manifestations of PIK3CA-related overgrowth spectrum who require systemic therapy. Despite all the existing regulatory guidelines considering real-world evidence (RWE), there is limited regulatory precedent of the use of this framework in support of a new indication. Thus, our case study illustrates design innovations based on the use of a compassionate use program, primarily in children, as a RWD source for approval of a new therapy in a rare disorder. We highlight the systematic considerations and mitigation of potential sources of bias in order to transform the data into actionable evidence. Our experience shows that RWE can be successfully used with appropriate study planning and mitigation in the context of a rare disorder with a high unmet medical need. Some lessons learned from this case study can benefit therapeutic development in rare disorders.

Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c.

Loss-of-function mutations of FIG4 are responsible for neurological disorders in human and mouse that result from reduced abundance of the signaling lipid PI(3,5)P2. In contrast, loss-of-function mutations of the phosphoinositide kinase PIP4K2C result in elevated abundance of PI(3,5)P2. These opposing effects on PI(3,5)P2 suggested that we might be able to compensate for deficiency of FIG4 by reducing expression of PIP4K2C. To test this hypothesis in a whole animal model, we generated triallelic mice with genotype Fig 4-/-, Pip4k2c+/-; these mice are null for Fig 4 and haploinsufficient for Pip4k2c. The neonatal lethality of Fig 4 null mice in the C57BL/6J strain background was rescued by reduced expression of Pip4k2c. The lysosome enlargement characteristic of Fig 4 null cells was also reduced by heterozygous loss of Pip4k2c. The data demonstrate interaction between these two genes, and suggest that inhibition of the kinase PIPK4C2 could be a target for treatment of FIG4 deficiency disorders such as Charcot-Marie-Tooth Type 4J and Yunis-Varón Syndrome.

Oral parafunction and bruxism in Rett syndrome and associated factors: An observational study.

OBJECTIVES: To explore patterns of parafunction, and bruxism, and its relationships with genotype and snoring in individuals with Rett syndrome (RTT). METHODS: Retrospective observational data of those with confirmed MECP2 mutations in the InterRett database (n = 216) were used to investigate experience of parafunctional habits, and bruxism and their relationships with genotype and snoring using multivariable linear regression. RESULTS: The prevalence of parafunction was 98.2%. Bruxism was reported (66.2%) with the patterns mostly both diurnal and nocturnal (44.1%) and exclusively diurnal (42.7%). Compared to individuals with C-terminal deletion, individuals with p.Arg106Trp mutations were less likely to have bruxism reported (aOR = 0.15; 95% CI 0.02-0.98, p = 0.05) and those with p.Arg168* mutation were more likely to have frequent bruxism than none or occasional bruxism reported (aROR 3.4; 95% CI 1.1-10.7 p = 0.04). The relative odds of having nocturnal bruxism constantly, compared to none/occasionally, were higher among those 'always' snoring (aROR 6.24; 95% CI 2.1-18.2, p = 0.001) than those with no snoring. CONCLUSIONS: There appeared to be genotypic association with bruxism in p.Arg168* and p.Arg106Trp mutations and association between nocturnal bruxism and frequent snoring in an international sample of individuals with RTT. Clinical significance of the high prevalence of bruxism should be highlighted in relation to difficulty communicating pain and increased dental treatment need in RTT.

Development of a Palliative Care Approach for Primary Progressive Aphasia: My Experience as a Person Living With This Rare Disorder.

Frontotemporal disorders are a group of rare young-onset dementias for which there is no cure, nor is there any way to slow the underlying progressive brain degeneration. To date those affected have typically received very little, if any, follow-up care after diagnosis, particularly in the early stages of their disease. I have received a clinical diagnosis, supported by imaging, of primary progressive aphasia, a form of frontotemporal degeneration characterized in the initial phase by progressive impairment of language ability. From the onset, I have been fortunate to receive excellent ongoing palliative care from a multidisciplinary team, some of whom had never previously seen anyone with this disorder. My quality of life has been enhanced by an evolving range of creative strategies and adaptations targeted to my deficits as they have arisen. In this paper, I discuss my experience of the process underlying this personalized plan, which serves as a paradigm for the development of novel palliative care approaches for people living with rare disorders, both neurodegenerative diseases and other conditions.

"If not me, who?": Awareness- and Self-Advocacy-Related Experiences of Adults With Diverse Rare Disorders.

In a two-study project, researchers used qualitative methods and inductive thematic analyses to investigate the lived awareness- and advocacy-related experiences of 27 adults with over 35 different rare diseases, disorders, or disabilities (RDs). In Study 1, participants in two focus groups described how a lack of RD awareness led to experiences with several types of stigma, complicated their expressions and disclosures of disability, and spurred them to work towards awareness. Participant priorities identified in Study 1 motivated researchers to design and conduct Study 2. In Study 2, researchers interviewed 18 RD self-advocates about their lived experiences with and ideas regarding advocacy. Their recommendations included increasing social and systemic support, education, and media and professional representation. Advocates in Study 2 also warned of potential roadblocks to self-advocacy and change, including systemic invalidation and bias, lack of access to activist spaces, and limited time and energy for advocacy. Overall, analyses exposed the complex and interwoven influences of RD awareness and advocacy.

Mental health and neurodevelopment in children and adolescents with Turner syndrome.

OBJECTIVES: Turner syndrome (TS) is a rare sex chromosome aneuploidy, with an incidence of four in 10,000 new-born girls. TS is often associated with impaired social communication skills, but the extent to which these are attributable to Autism Spectrum Disorders (ASD) is uncertain. We made standardized assessments of the mental health and associated neurodevelopmental disorders in children and adolescents with TS and report on the prevalence of concurrent conditions. METHODS: Our sample comprised 127 girls with TS, 5-19 years of age. We obtained reports of their mental health from a combination of diagnostic interview (the Development and Wellbeing Assessment (DAWBA)), from the Strengths and Difficulties Questionnaire (SDQ) and from the Social Responsiveness Scale (SRS-2). Sources of information included parents, teachers and self-reports. The prevalence of mental health disorders in this sample was compared with age/sex matched national English data from typical controls. RESULTS: Most individuals with TS (83%) had experienced significant social communication difficulties and nearly one in four (23%) met diagnostic criteria for ASD on the DAWBA. One-third (34%) had at least one mental health or neurodevelopmental condition, and those girls with an ASD were at a greater risk of a co-occurring emotional disorder and/or attention deficit hyperactivity disorder (ADHD). CONCLUSION: Children and adolescents with TS are substantially more likely to meet criteria for ASD than their typically developing peers. Our finding has clinical implications for appropriate behavioural management from preschool through to adolescence.

Suspecting and diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM) in India: An Indian expert consensus.

Transthyretin cardiac amyloidosis (ATTR-CM) is a rare and under-recognized disorder characterized by the aggregation of transthyretin-derived insoluble amyloid fibrils in the myocardium. Heterogeneity of symptoms at presentation, makes its diagnosis often delayed. An expert panel gathered on a virtual platform across India to conduct a meeting for developing a guiding tool for ATTR-CM diagnosis. The panel recommended younger age (≥40 years) for suspecting ATTR-CM and thick-walled non-dilated hypokinetic ventricle was considered as one of the important red flags. Electrocardiogram (ECG) and echocardiography (ECHO) findings were recommended as primary tests to raise the suspicion while nuclear scintigraphy and hematological tests were recommended to confirm the diagnosis and rule out amyloid light-chain (AL) amyloidosis. Cardiac magnetic resonance (CMR) and biopsy were recommended in case of ambiguity in the presence of red flags. Considering the lack of expert guidelines in the Indian scenario, a standardized diagnostic algorithm was also proposed.