Need For Genetic Counseling Research Articles

A survey to analyze the need of genetic counseling among doctors in Lahore, Pakistan.

Pakistan with a population of approximately 200 million people faces a significant burden of genetic disorders. Higher preference for consanguinity (73%) is one of the significant reasons. Despite being a hub for rare genetic disorders, the country lacks professionally trained genetic counselors due to the absence of postgraduate degree programs or diplomas in genetic counseling. This shortage of specialized personnel results in inadequate and limited genetic counseling practices nationwide. This study aimed to highlight the urgent need for genetic counseling in Pakistan, focusing on the gaps within both society and the healthcare infrastructure. A survey-based study involving n = 101 participants was conducted to assess the demand for genetic counseling among medical professionals in Lahore, Pakistan. The study targeted five categories of medical specialists-gynecologists, oncologists, psychiatrists, pediatricians, and ultrasonologists-working in both private and public healthcare settings in Lahore. The survey included a questionnaire covering demographic information, 10 general questions, and a case study with follow-up questions. The survey was conducted both online and through in-person visits. Our findings reveal a significant lack of awareness among healthcare providers, with 91.1% of respondents unaware of any genetic counseling services or genetic counselors in Lahore. The research underscores the crucial role of genetic counselors, with the vast majority (99%) of specialists expressing an urgent need for their presence in Pakistan's healthcare system. This study highlights that only qualified genetic counselors can effectively address genetic issues. Furthermore, it advocates for the introduction of specialized professional training programs to address this pressing need in the country.

Clinical and molecular cytogenetic findings of cat eye syndrome and a 2-year-old patient with congenital aural atresia and hearing loss

BackgroundCat eye syndrome (CES) is a rare congenital disease frequently caused by a partial tetrasomy of the proximal long (q) arm of chromosome 22, due to a small supernumerary marker chromosome (sSMC). CES patients show remarkable phenotypic variability. Despite the progress of molecular cytogenetic technology, the cause of phenotypic variability and the genotype–phenotype correlations remain unknown.MethodsWe analyzed clinical and genetic data of a new patient with CES together with 27 previously reported ones with a confirmed genomic gain in the PubMed database between 2012 and 2023.ResultsWe reported a boy with CES carrying a 22q11.1-q11.21 duplication of 1.76 Mb tetrasomy (16888900_18644241, hg19) who presented currently rare or unreported clinical findings such as congenital aural atresia, hearing loss, PLSVC, and IVC. The results of the whole exome sequencing (WES) showed a heterozygous mutation of the GJB2 gene (NM_004004.6: exon2: c.109G > A). In addition, the results of our literature review showed that the presence of a classical sSMC was the most frequent cytogenetic abnormality in CES (82%). 63% of cases were in a homogenous state and 37% of cases were in a mosaic state. 72% of cases had a 1–2 Mb duplication. In the majority of CES patients the breakpoints in chromosome 22 are localized to a 50 kb region (18610000_18660000 bp). The CES critical region (CESCR) may be further delimited to a 0.3 Mb region (17799398_18111588 bp). Within this region CECR2, SLC25A18, ATP6V1E1, and BCL2L13 are strong candidate genes for causing the main CES phenotype. The ear anomalies are the most frequent features in CES patients (89%) and hearing loss was present in 36% of CES patients.ConclusionsThe phenotypic features in CES are highly variable. Our findings expand the symptom spectrum of CES and lay the foundation for better delineating the clinical phenotype, molecular cytogenetic features associated with CES and genotype–phenotype correlations. We recommend performing WES to rule out the involvement of other genetic factors in the patient’s phenotype. In addition, our findings also highlight the need for genetic counseling and recurrence risk assessment.

Hemoglobinopathy for Malaria Protection: A Comprehensive Review

Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia, are inherited disorders that affect hemoglobin structure and function, leading to significant health implications. However, these genetic conditions also confer a degree of protection against malaria, particularly Plasmodium falciparum, the most virulent malaria parasite. This comprehensive review examines the relationship between hemoglobinopathies and malaria protection, exploring how genetic mutations in hemoglobin subunits influence susceptibility to malaria. Sickle cell trait (HbAS) provides notable protection against severe malaria, with mechanisms including reduced parasite growth, enhanced immune clearance, and microvascular obstruction. Although homozygous sickle cell disease (HbSS) does not confer protection and leads to severe complications, the high prevalence of HbS in malaria-endemic regions underscores an evolutionary balance. Thalassemia, both alpha and beta types, also offers partial malaria protection by altering the red blood cell environment, though the precise mechanisms remain less understood. Additionally, other hemoglobin variants, such as hemoglobin C (HbC) and hemoglobin E (HbE), demonstrate varying degrees of malaria resistance. The review highlights the evolutionary and epidemiological evidence supporting the protective effects of these genetic traits, emphasizing their role in malaria-endemic regions. Public health implications include the need for genetic counseling and targeted malaria control strategies. Future research directions include elucidating mechanistic pathways, exploring regional variations, and assessing the impact on malaria vaccine efficacy. By integrating insights from hemoglobinopathy research into public health interventions, more effective malaria control strategies can be developed, ultimately improving health outcomes for affected populations. Keywords: Hemoglobinopathies, Sickle Cell Disease, Thalassemia, Malaria Protection, Plasmodium falciparum.

Evaluation of Metabolic and Biochemical Abnormalities in Pediatric Population With Nephrocalcinosis in Southwestern Iran

This retrospective study aimed to evaluate the metabolic and biochemical abnormalities in children with nephrocalcinosis to identify its important risk factors and better understand the disease pathophysiology. Data were collected from the medical records of 163 children diagnosed with nephrocalcinosis. Their clinical and laboratory characteristics at admission were recorded, and a 24-hour urinalysis was performed to measure parameters such as calcium, oxalate, citrate, uric acid, magnesium, and cystine. Family history of kidney stones and parental consanguinity were present in 58.8% and 58.2% of patients, respectively. The most common underlying conditions were hyperparathyroidism (24%), distal renal tubular acidosis (16.6%), and medullary sponge kidney (12.9%). The main abnormalities included hypocitraturia (65.2%), hypercalciuria (51.9%), hypomagnesuria (44.6%), hyperoxaluria (39.1%), hyperuricosuria (31.5%), vitamin D deficiency (30.06%), and metabolic acidosis (27%). Patients with kidney stones and failure to thrive had higher rates of hypercalciuria. Metabolic acidosis was more common in those with parental consanguinity and vitamin D deficiency. Renal failure at final follow-up was more evident in older patients, those with parental consanguinity, hypokalemia, acidosis, and hyperparathyroidism. End-stage renal disease was more frequent in patients with consanguineous parentage, hyperparathyroidism, hypokalemia, and acidosis. Parental consanguinity, family history of kidney stones, and urinary metabolic disorders are important risk factors for pediatric nephrocalcinosis. This highlights the need for genetic counseling, screening, and monitoring of biochemical abnormalities. Early diagnosis and timely treatment are crucial to maintain glomerular function and prevent kidney failure.

“A Call To Action”: The need for genetic counseling in Uganda

“A Call To Action”: The need for genetic counseling in Uganda

Compound heterozygous ABCA12 variants identified in a Chinese patient with congenital ichthyosiform erythroderma: Advancing genotype-phenotype correlations and literature review.

Ichthyosis is a common keratotic skin disease with high clinical, etiological and genetic heterogeneity. There are four types of non-syndromic hereditary ichthyoses, among which autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of recessive Mendelian disorders. ARCI present with different phenotypes and ABCA12 pathogenic variants have been shown to cause complex ARCI phenotypes, including harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A sporadic male patient, clinically diagnosed with CIE, was enrolled in this study. Exome sequencing was combined with Sanger sequencing to confirm the diagnosis and identify the pathogenic variants. In silico predictions were made using multiple software programs, and the identified variants were interpreted using the ACMG guidelines. A review of all literature reported ABCA12 variants was performed to explore genotype-phenotype correlations. Compound heterozygous ABCA12 variants [c.5381+1G>A and c.5485G>C (p.Asp1829His)] (NM_173076) were identified. The two variants were not detected in the public database. c.5381+1G>A is predicted to affect ABCA12 mRNA splicing and Asp1829 is highly conserved among various species. In silico analysis suggested that these two variants were responsible for the phenotype of the patient. Genotype-phenotype correlation analysis showed that biallelic truncation variants and/or exon/amino acid deletions in ABCA12 are the most common causes of HI. Biallelic missense variants are most common in LI and CIE. The compound heterozygous ABCA12 variants caused the CIE phenotype observed in the patient. The spectrum of ABCA12 pathogenic variants were broaden. Genotype-phenotype correlation analysis provided detailed evidence which can be used in future prenatal diagnosis and can inform the need for genetic counselling for patients with ABCA12-related ARCIs.

Attitudes of medical professionals toward fragile X carrier screening and genetic counseling in China.

Fragile X syndrome is the most common inherited cause of intellectual disability. Considering China's low prevalence, distinct healthcare system, middle-income economic status, and unique culture, China cannot simply replicate the screening systems in European and American countries. In this study, we investigated the attitudes of 450 Chinese medical professionals who received fragile X training on fragile X carrier screening and genetic counseling. Before the training, 57.6% of the respondents were unfamiliar with FXS. After the training, 7.3% of participants are unable to fully master the knowledge. Furthermore, 71.8% believe that the absence of phenotypes during the reproductive age and the availability of simple and feasible testing methods are prerequisites for screening. The presence of the phenotype would still require screening. Regarding the target population, over 90% of the participants support fragile X carrier screening in high-risk pregnant women. As for influencing factors, they consider cost as the most influential factor in pregnant women's decision to undergo screening. The acceptable price range for screening is determined to be ￥200-1000 ($30-150). In terms of the issues and challenges of screening, most medical professionals support the need for genetic counseling for intermediate alleles and 55-60 repeat premutation results. Additionally, some respondents believe that informing patients' family members of positive screening results is necessary. It is also recognized that positive results may lead to anxiety for patients. The findings of this study will provide valuable information for the establishment of fragile X carrier screening system, particularly for low-prevalence or middle-income countries.

Prevalence and risk factors of vitiligo in Saudi Arabia: a systematic review

The purpose of this study was to determine the risk factors and prevalence of vitiligo in the Saudi population. A comprehensive computerized search of pertinent databases was carried out to find research that satisfied the requirements of inclusion. To locate relevant studies, PubMed, SCOPUS, Science Direct, Cochrane Library, and Web of Science were all searched. The prevalence of vitiligo among the Saudi population ranged from 0% among school children to 7%. The results indicated that genetic factors, such as family history and parental consanguinity, contribute significantly to the vitiligo prevalence in Saudi Arabia. Localized vitiligo was the most common form, with stress identified as a key trigger for disease progression. Consanguinity in marriages further increased disease prevalence, highlighting the need for genetic counseling and public awareness programs to reduce the impact of vitiligo. This study emphasized the contribution of stress and genetic predisposition to the development of vitiligo in the Saudi population. By focusing on these factors, healthcare providers can improve prevention and management strategies through genetic counseling, stress management, and community education. However, future research with more extensive population data and deeper exploration of various risk factors is essential to refine these strategies and enhance patient care.

Prenatal evaluation of genetic variants in fetuses with small head circumference: A single-center retrospective study

Objectives: To comprehensively evaluate the contributions of numerical chromosomal abnormality, copy number variant (CNV), and sequence variant (SV) to fetuses with small head circumference in a Chinese cohort using chromosome microarray analysis and whole exome sequencing. Methods: A total of 157 fetuses with small heads defined as head circumference < − 2 standard deviation (SD) were recruited between October 2014 and March 2023. We used the ultrasonic measurement parameter Z-score to define small head as possible microcephaly (3 < Z ≤ -2), microcephaly (-5 < Z ≤ -3), or pathologic microcephaly (Z ≤ -5). Ultrasound findings and genetic results were analyzed. Results: The overall diagnostic yield of chromosomal abnormalities by microarray analysis was 13 %. Whole exome sequencing revealed eight novel variants and two interesting candidate genes and provided a 25.4 % incremental yield compared with microarray analysis. Of the detected SVs, 56 % were de novo and the most common inheritance pattern was autosomal dominant inheritance presented in 11/16 fetuses. Compared with isolated small heads, non-isolated small heads had a significantly higher detection rate of chromosomal abnormalities (16 % vs. 3.0 %, P = 0.049) but not SVs (24 % vs. 5.5 %, P = 0.126). Subgroup analysis showed that intracranial anomalies had a similar high detection rate of SVs in fetuses with all small heads subgroups while no chromosomal abnormalities and causative SVs were found in fetuses with isolated possible microcephaly. Conclusions: Ultrasound findings of small fetal head circumference < 3 SD below the mean, especially those with intracranial structural abnormalities, indicate the need for genetic counseling. Genetic variants, mainly copy number variants and SV, may be responsible for the substantial proportion of small fetal head circumference, while most are de novo. Whole exome sequencing and microarray analysis are effective diagnostic approaches for this population.

Cat eye syndrome: Clinical, cytogenetics and familial findings in a large cohort of 43 patients highlighting the importance of congenital heart disease and inherited cases.

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.

Referral, Uptake, and Outcome of Genetic Counseling and Testing in Patients With Early-Onset Colorectal Cancer.

The incidence of early-onset colorectal cancer (EOCRC) is rapidly increasing. Pathogenic germline variants (PGVs) are detected in 16% to 20% of patients who have EOCRC, highlighting a need for genetic counseling (GC) and multigene panel testing in these patients. We aimed to determine the rate of referral to GC and uptake and outcomes of germline testing in patients with EOCRC. We conducted a retrospective cohort study of patients aged <50 years diagnosed with colorectal cancer (CRC) from 2010 to 2019 at Cleveland Clinic. Demographic data were extracted, including age, sex, self-reported race, and family history of CRC. The proportions of patients with GC referral and completion of GC and genetic testing were investigated, and genetic testing results were analyzed. Multivariable logistic regression analysis was conducted to identify factors independently associated with GC referral and uptake. A total of 791 patients with EOCRC (57% male and 43% female) were included; 62% were referred for GC, and of those who were referred, 79% completed a GC appointment and 77% underwent genetic testing. Of those who underwent testing, 21% had a PGV detected; 82% were in known CRC-associated genes, with those associated with Lynch syndrome and familial adenomatous polyposis the most common, and 11% were in other actionable genes. Referral to GC was positively associated with family history of CRC (odds ratio [OR], 2.11; 95% CI, 1.51-2.96) and more recent year of diagnosis (2010-2013 vs 2017-2019; OR, 5.36; 95% CI, 3.59-8.01) but negatively associated with older age at diagnosis (OR, 0.89; 95% CI, 0.86-0.92). Referral to GC for patients with EOCRC is increasing over time; however, even in recent years, almost 25% of patients were not referred for GC. We found that 1 in 5 patients with EOCRC carry actionable PGVs, highlighting the need for health systems to implement care pathways to optimize GC referral and testing in all patients with EOCRC.

SAT603 A Heterogeneous Genetic Background Underlies Familial And Young-onset Pituitary Tumors

Abstract Disclosure: J.M. Zuarth-Vazquez: None. R.G. Rebollar-Vega: None. C. Ramírez-Rentería: None. W.E. Hernández-Núñez: None. M. Torres-Morán: None. A.L. Franco-Álvarez: None. J. Eseiza-Acevedo: None. M. Aguilar-Soto: None. D. Cuevas-Ramos: None. E. Sosa-Eroza: None. M. Mercado: None. A. Gamboa-Dominguez: None. L.C. Hernández-Ramírez: None. Introduction: Inherited pituitary neuroendocrine tumors (PitNETs) are considered rare and may present either as isolated lesions or in association with other endocrine tumors. Despite significant progress in the understanding of their molecular basis, the precise pathophysiological mechanisms in many patients with familial and sporadic pituitary tumors are unknown. Although the clinical presentation may point towards a specific genetic cause, a combination of careful clinical assessment and state-of-the-art genetic testing is required. Objective: To describe 4 cases of PitNETs with heterogeneous clinical presentations and genetic causes from a cohort of Mexican patients with neuroendocrine tumors. Methodology: Patients were recruited under informed consent from two different reference hospitals in Mexico City. Germline genetic testing was performed using either a custom-made or a commercial next-generation sequencing (NGS) panel. When available, relevant variants were confirmed in tissue samples. Genetic results were correlated with clinical, biochemical, and imaging characteristics. Results: Case 1 is an 18-year-old male with gigantism due to a 3-cm GH/prolactin-secreting PitNET, that was not cured after transsphenoidal surgery (TSS). Genetic testing showed a CDKN1B (NM_004064.5) c.356T&amp;gt;C, p.I119T variant of uncertain significance. No relevant family history was informed. Currently, the patient is treated with monthly octreotide LAR. Case 2 is a patient with young-onset acromegaly (15y) due to a GH-secreting PitNET. She was initially treated with bromocriptine and then underwent TSS without achieving remission. Radiotherapy was therefore indicated, resulting in panhypopituitarism. The likely pathogenic variant of AIP (NM_003977.4) c.872_877del, p.V291_L292del, was identified. Case 3 was diagnosed at the age of 15 with gigantism, treated with TSS and radiotherapy, subsequently demonstrating biochemical cure. Whole-exome sequencing showed the AIP pathogenic variant c.910C.T, p.R304*, indicative of familial isolated pituitary adenoma, confirmed by the history of two paternal first cousins with gigantism. Finally, a 54-year-old man (case 4), with a personal and family history of neurofibromatosis type 1, was incidentally diagnosed with a 16 mm, apparently non-functional PitNET, for which he is awaiting surgery. The pathogenic NF1 (NM_001042492.3) variant c.147C&amp;gt;A, p.Y49* was identified. Conclusions: Our data confirm that inherited PitNETs encompass a variety of clinical phenotypes. Modern NGS-based genetic testing is an effective method for identifying such cases. Precise molecular testing has an impact on the timely diagnosis of these lesions, as well as on their prognosis and the need for genetic counseling. Presentation: Saturday, June 17, 2023

A 13-Month-Old Iranian Boy with Thrombosis of the Left Transverse and Superior Sagittal Sinuses Due to Homozygous Mutations in MTHFR A1298C: A Case Report &amp; Review of Literature

Background and Aims: Cerebral sinus venous thrombosis (CSVT) is a rare stroke subtype in children, with limited data on its clinical presentation, etiology, and outcomes. This case report aims to describe a case of CSVT in a child, including their clinical presentation, imaging findings, and management, to increase awareness of this rare but serious condition. Case presentation: A 13-month-old boy presented with swelling and deviation of the left eye after being hospitalized for left periorbital cellulitis. The patient was diagnosed with thrombosis of the left transverse and superior sagittal sinuses and underwent treatment with levetiracetam, folinic acid, rosuvastatin and enoxaparin followed by warfarin. Genetic testing was also performed to identify the underlying genetic basis of thrombophilia. Results: Laboratory tests showed that there was one heterozygous mutation in the β-Fibrinogen gene and three homozygous mutations in MTHFR A1298C, PAI-I-675 4G/5G, and PAI-I-844 G/A genes. Additionally, Lipoprotein (a) was measured at 89.3 nmol/L and the patient's mother had two homozygous mutations in PAI-I-675 4G/5G and PAI-I-844 G/A genes. Conclusions: It appears that the mutation in MTHFR gene is more prevalent in our region, which may be a contributing factor to the increased incidence of stroke in children and adolescents in the country. Further research is needed to determine the prevalence of this mutation and its impact on thrombophilia in the population. This case highlights the importance of prompt diagnosis and treatment of CSVT in children, as well as the need for genetic counselling and testing to identify underlying risk factors.

Outcomes of two different unbalanced segregations from a maternal t(4;10)(q33;p15.1) translocation

BackgroundUnbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances.MethodsWe performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features.ResultsThe proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1).ConclusionTo our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling.

Recent approaches on Huntington's disease (Review).

Huntington's disease (HD) is a neurodegenerative disorder characterized by severe motor, cognitive and psychiatric symptoms. Patients of all ages can present with a dysfunction of the nervous system, which leads to the progressive loss of movement control and disabilities in speech, swallowing, communications, etc. The molecular basis of the disease is well-known, as HD is related to a mutated gene, a trinucleotide expansion, which encodes to the huntingtin protein. This protein is linked to neurogenesis and the loss of its function leads to neurodegenerative disorders. Although the genetic cause of the disorder has been known for decades, no effective treatment is yet available to prevent onset or to eliminate the progression of symptoms. Thus, the present review focused on the development of novel methods for the timely and accurate diagnosis of HD in an aim to aid the development of therapies which may reduce the severity of the symptoms and control their progression. The majority of the therapies include gene-silencing mechanisms of the mutated huntingtin gene aiming to suppress its expression, and the use of various substances as drugs with highly promising results. In the present review, the latest approaches on the diagnosis of HD are discussed along with the need for genetic counseling and an up-to-date presentation of the applied treatments.

Assessment of Concurrent Personal and Family History of Hematologic Malignancies in Patients Referred for Genetic Counseling at Thomas Jefferson University Hospital (TJUH), Sidney Kimmel Cancer Center (SKCC) from 2014-2021

Introduction: Studies have suggested that 5% of adult patients with MDS and AML have inherited mutant alleles that predispose to disease development. More than 50 hereditary cancer syndromes have been defined-many specifically associated with myeloid and lymphoid malignancies. Yet hereditary hematologic malignancies (HHMs) continue to go unrecognized. The implications for patients, especially regarding family donor selection for allogeneic stem cell transplant, necessitate greater awareness. Referrals for genetic counseling at SKCC have been triggered primarily by a personal or family history of solid tumors. The aim of this study was to assess the frequency of hematologic malignancies in the setting of concurrent solid tumor diagnosis or significant family history of cancer. Methods: In order to gain preliminary insight into the unmet need for genetic counseling for HHMs at our institution, we queried our Cancer Genetics REDCap database (IRB-approved #16D.743) for all patients who had a cancer diagnosis, a family history of cancer, and a hematologic malignancy (HM). Cancer diagnoses and family history were collected at time of genetic counseling by a genetic counselor and were primarily patient reported. After identifying patients with self-reported HMs, HM diagnoses were confirmed by medical history and pathology report, if available, in our electronic medical record system. Results: The database included 5073 patients who were evaluated at SKCC's Cancer Genetics Program between 2014 and 2021. 3150 patients had a known cancer diagnosis including: breast (1812), prostate (349), ovarian (219), colon/rectal (218), pancreatic (157), melanoma (123), kidney (83), lung (18), and other (708). 4734 patients had a family history of cancer. 2913 patients had both a personal cancer diagnosis and a family history of cancer. Overall, 58 (2%) of these patients had a hematologic malignancy. Among patients with a HM, average age at HM diagnosis was 47 years (median 50, range 5-80) and average age at time of genetics counseling was 60 years (median 63.5, range 35-83). 48 of the patients were female. 51 were White/Caucasian, 6 were Black/African American, and 1 was Asian. 1 patient was Hispanic and 8 patients were Ashkenazi Jewish. There was a wide range of HM diagnoses (Table 1). 39 (67%) patients had a concurrent solid malignancy. The 58 patients with a HM and family history of cancer had on average 5.2 family members with a malignancy (median 4, range 1-14). 53 (91.4%) of the patients had at least 1 first degree relative with a malignancy (Table 2). 17 (29%) patients had a family member with a known HM, including 11 (19%) with a first degree relative. HMs identified among first and second degree relatives included: CLL (N=5) Non-Hodgkin lymphoma (N=3), Hodgkin lymphoma (N=3), Waldenstrom macroglobulinemia (N=2), lymphoma not otherwise specified (N=3), AML (N=1), leukemia NOS (N=3), multiple myeloma (N=2), and polycythemia transformed to myelofibrosis (N=1). Of the 40 HM patients who had germline genetic testing performed, alterations were identified in 22. 10 of the patients had 11 pathogenic or likely pathogenic variants in CHEK2, ATM, FANCC, NBN, MSH2, MSH6, BRCA2, and/or FH. 6 (60%) of these patients had alterations in genes known to be associated with HHMs. 21 variants of unknown significance were identified in 14 patients, including in 2 patients with pathogenic variants. Conclusions: Approximately 2% of patients referred for genetic counseling for a personal malignancy and family history of cancer had a concurrent diagnosis of a HM. This likely under-represents the number of patients with HHMs, particularly since 6 of the 10 patients identified to have pathogenic or likely pathogenic variants had alterations in genes associated with HHMs. The findings that 67% of the HM patients had a second malignancy and that HM patients had on average 5 family members with cancer highlight the importance of identifying high risk patients to guide surveillance for earlier detection. Earlier recognition is crucial, as the average age of genetics counseling was 60. Despite striking family cancer histories, germline variants were not identified in several patients, suggesting that there may be germline variants that have yet to be identified. Efforts to expand genetic screening that focus on earlier identification, standardized germline testing for high risk patients, and appropriate surveillance will be important. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S244 An Appraisal of the Referral, Uptake and Outcomes of Genetic Counseling and Testing in Patients With Young Onset Colorectal Cancer

Introduction: The incidence of young-onset colorectal cancer (YOCRC) defined as CRC in individuals < 50 years of age is rapidly rising. Germline genetic testing is currently recommended for all patients with CRC< 50 years. Germline pathogenic variants (PV) are detected in 16-20% of patients with YOCRC and many are diagnosed with an actionable PV not typically associated with CRC, highlighting a need for genetic counseling and multi-panel gene testing (MGPT) in these patients. We aimed to determine the rate of referral to genetic counseling, and uptake and outcomes of germline testing in YOCRC patients seen at a tertiary referral center. Methods: Patients diagnosed with YOCRC from 2010-2019 were included. Patients with appendiceal cancer, known family history of a hereditary cancer syndrome and inflammatory bowel disease were excluded. Demographic data including age, sex, race and family history of CRC were extracted from the electronic medical record (EMR).Genetic counseling referral was confirmed through an order in the EMR, clinical documentation in office visits with colorectal surgery, oncology or gastroenterology, or a completed visit with the genetic counselor. Data was analyzed using STATA, Chi-square and t-test and descriptive analyses were included. Results: 793 YOCRC patients (457 male and 336 female) were included. 56% (445) were referred for genetic counseling and 88% of referred patients completed genetic testing. 20.5% had a PV detected; 83% were in CRC associated genes and 18% were in other actionable genes (Table). Referral to genetic counseling was higher in younger patients (mean age= 40 years in those referred vs. mean age= 43 years in those not referred, p < 0.05) and those with a family history of CRC (70% of patients with family history of CRC vs. 53% of patients without family history were referred, p< 0.05) There was no significant association between referral rate and sex or race. Conclusion: Even in a large academic center, the rates of referrals for genetic counseling in patients with YOCRC were documented in only about half the patients. 1 in 5 YOCRC patients had a PV detected. If the 348 patients not referred to genetic counseling underwent testing, an additional 71 patients may be detected with a germline PV. Our findings highlight the need to raise awareness of the importance of genetic counseling and testing in YOCRC patients, and suggest that health systems should consider implementing care pathways to mitigate the potential impact of under-referral. Table 1. - Demographics, Referral to and Uptake of Genetic Counseling and Testing and Outcome of Genetic Testing Number of patients with YOCRC 793 Demographics N (%) Mean (SD) Age 41.9 (6.8) Sex Male 457 (57.6) Female 336 (42.4) Race White 684 (86.3) Black 72 (9.1) Other 37 (4.7) Family History of CRC Yes 280 (40.2) No 417 (59.8) Referral for Genetic Counseling 445 (56.1) Attended Genetic Counseling 390 (87.6) Underwent Genetic Testing 376 (96.4) • Pathogenic Variant Detected 77 (20.5) • Variant of Uncertain Significance Detected 88 (23.4) • No Variant Detected 211 (56.1) Genetic Testing Outcomes Genetic Syndrome Pathogenic Variant Number of Patients Total (%) CRC and polyposis genes N=64 (83%) Lynch syndrome N=37 (48%) MLH1 11 37 (48) MSH2 13 MSH6 8 PMS2 5 FAP N= 15 (19.4%) APC 15 15 (19.4) MYH- Associated polyposis N =10 (12.9%) MUTYH (Biallelic) 6 10 (12.9) MUTYH (Monoallelic) 4 Juvenile polyposis syndrome N = 1 (1.2%) SMAD4 1 1 (1.2) MSH3 (monoallelic) 1 1 (1.2) Other genes N=13 (17%) ATM 4 13 (17) BRCA1/2 4 BLM (monoallelic) 1 CHEK2 2 FLCN 1 CDKN2A 1

32P BRCA1/2 mutations in epithelial ovarian cancer: Treatment response and survival analysis in a Spanish tertiary University Hospital

The presence of germline or somatic BRCA1/2 mutation (gBRCA1/2 or sBRCA1/2) on epithelial ovarian cancer (EOC) patients (pts) improves progression-free survival (PFS) and overall survival (OS). BRCAm is the only validated molecular biomarker both prognostic and predictive of platinum and PARPi response. Identification of these pts is already mandatory to optimize treatment strategies and the need for genetic counselling. We aimed to describe our BRCAm EOC population to analyse tumor response and survival outcomes.

Early onset obesity due to a mutation in the human leptin receptor gene.

SummaryLeptin is secreted by adipocytes in response to fat storage and binds to its receptor (LEPR), which is ubiquitously expressed throughout the body. Leptin regulates energy expenditure and is anorexigenic. In this study, we describe the clinical and hormonal findings of three siblings with a personal history of rapid weight gain during the first months of life. They had delayed puberty, high levels of FSH (15.6 ± 3.7 mUI/mL; reference: 1.5–12.4) and LH (12.3 ± 2.2 mUI/mL; reference: 1.7–8.6), normal oestradiol and total testosterone and successful fertility. None of the patients had dyslipidemia, diabetes or thyroid disease. Next-generation sequencing identified a pathogenic homozygous variant c.2357T>C, p.(Leu786Pro) in LEPR. Their parents and children were heterozygous for this mutation. We compared clinical and biochemical findings of homozygous carriers with first-degree heterozygous family members and ten randomly selected patients with adult-onset morbid obesity. Homozygous carriers of the mutation had significantly higher BMI (32.2 ± 1.7 kg/m2 vs 44.5 ± 7.1 kg/m2, P = 0.023) and increased serum levels of leptin (26.3 ± 9.3 ng/mL vs 80 ± 36.4 ng/mL, P = 0.028) than their heterozygous relatives. Compared with the ten patients with adult-onset morbid obesity, serum levels of leptin were not significantly higher in homozygous carriers (53.8 ± 24.1 ng/mL vs 80 ± 36.4 ng/mL, P = 0.149), and thus serum levels of leptin were not a useful discriminative marker of LEPR mutations. We described a rare three-generation family with monogenic obesity due to a mutation in LEPR. Patients with early onset obesity should be considered for genetic screening, as the identification of mutations may allow personalized treatment options (e.g. MC4R-agonists) and targeted successful weight loss.Learning pointsThe early diagnosis of monogenic forms of obesity can be of great interest since new treatments for these conditions are becoming available.Since BMI and leptin levels in patients with leptin receptor mutations are not significantly different from those found in randomly selected morbid obese patients, a careful medical history is mandatory to suspect this condition.Loss of leptin receptor function has been associated with infertility. However, our patients were able to conceive, emphasizing the need for genetic counselling in affected patients with this condition.

Whole-exome sequencing as a diagnostic tool for ipex syndrome

Immune dysregulation-Polyendocrinopathy-Enteropathy-X-linked (IPEX) syndrome is a life-threatening congenital autoimmune disorder caused by mutations in the forkhead box protein 3 (FOXP3) gene. Typical clinical manifestations of IPEX patients are early onset of intractable diarrhea, type 1 diabetes mellitus, and skin diseases. However, other autoimmune types such as severe food allergies, autoimmune cytopenias, autoimmune respiratory illness, and mesangial glomerulonephritis may complicate IPEX diagnosis. In this study, we report a Vietnamese 1-year-old boy with IPEX syndrome due to a hemizygous missense mutation, c.1190G&gt;A (p.Arg397Gln), in exon 12 of the FOXP3 gene (NM_014009.4). The child had dermatitis, diarrhea, respiratory infections, and splenomegaly. The patient's serum routine test results were expected, except for white blood cells and neutrophils were higher than the normal, while IgA concentration was slightly below the normal range. However, he got no signal of diabetes or failure to thrive. Whole exome sequencing was applied to identify a genetic variant, and variant validation was examined using Sanger sequencing. The patient’s genetic mutation was inherited from his mother, an obligate carrier. His father had a normal genotype. This study is the first report of IPEX syndrome in a Vietnamese patient with a mutation in the FOXP3 gene detected by WES. This study provides further evidence for the role of mutations in the FOXP3 gene in patients with IPEX syndrome and demonstrates the need for genetic counselling and prenatal testing. Our results also show that WES sequencing is an effective tool in diagnosing genetic diseases.