Rare Genetic Cause Research Articles

Phospholamban Cardiomyopathy Leading to Advanced Heart Failure in an Active Duty Service Member.

A phospholamban mutation is a rare genetic cause of dilated cardiomyopathy (DCM). Our case describes a young service member who presented with advanced heart failure and was found to have a familial DCM from an autosomal dominant phospholamban mutation. He ultimately underwent a successful heart transplant just 23 days after his initial presentation. This case highlights the importance of genetic screening and surveillance for patients with a family history of DCM, and it identifies a gap in medical standards for military accession.

The potential and translational application of infant genetic research.

In the current genomic revolution, the infancy life stage is the most neglected. Although clinical genetics recognizes the value of early identification in infancy of rare genetic causes of disorders and delay, common genetic variation is almost completely ignored in research on infant behavioral and neurodevelopmental traits. In this Perspective, we argue for a much-needed surge in research on common genetic variation influencing infant neurodevelopment and behavior, findings that would be relevant for all children. We now see convincing evidence from different research designs to suggest that developmental milestones, skills and behaviors of infants are heritable and thus are suitable candidates for gene-discovery research. We highlight the resources available to the field, including genotyped infant cohorts, and we outline, with recommendations, special considerations needed for infant data. Therefore, infant genetic research has the potential to impact basic science and to affect educational policy, public health and clinical practice.

REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.

Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

Motor difficulties in 16p11.2 copy number variation.

The rare genetic variants 16p11.2 duplication and 16p11.2 deletion have opposing effects on brain structure and function, yet are associated with broadly similar clinical phenotypes that include autism, intellectual impairment, psychiatric illness, and motor difficulties. In recent years, studies have identified subtle distinctions between the phenotypic effects of 16p11.2 duplication and 16p11.2 deletion with respect to patterns of autism, intellectual impairment, and psychiatric illness. However, although divergent phenotypic findings in some motor domains have been reported, no study has yet made a comprehensive comparison of motor difficulties between 16p11.2 deletion and 16p11.2 duplication carriers to elucidate points of convergence and divergence. We sought to make such a comparison in a group of 133 16p11.2 deletion carriers, 122 duplication carriers, and 388 familial controls, hypothesizing that motor impairment would overall be greater in deletion than duplication carriers. In a series of regression models, we found that 16p11.2 deletion status tended to predict greater impairment along indices of gross motor function, but less impairment along indices of fine motor function. These findings point to a potential pattern of performance difficulties that could be investigated in future studies. Elucidating motor differences between 16p11.2 duplication and 16p11.2 deletion carriers may help in understanding the complex effect of 16p11.2 copy number variation and other rare genetic causes of autism.

Prevalence and <em>in silico</em> analysis of p.D658G variant of WDR36 gene in patients affected with primary open angle glaucoma from Punjab Pakistan

The aim of the present study was to check the frequency of genetic variants in exons 8, 11, 13, and 17 of the WDR36 gene among primary open angle glaucoma (POAG) patients from Punjab, Pakistan, and to perform the in silico analysis of identified variants on protein function. Ninety-two individuals affected with primary open angle glaucoma were enrolled for this study. The clinical investigation involved the examination of the optic nerve head, visual field loss and elevated intraocular pressure (IOP). Selected exons (8, 11, 13, and 17) of the WDR36 gene was screened by Sanger sequencing. Sequencing results revealed a previously reported missense mutation p.D658G in exon 17 in two out of ninety-two POAG patients, while no mutation has been identified in the exons 8, 11, and 13. To predict the structural and functional effect of the p.D658G variant, SIFT, Polyphen-2, PROVEAN, mutation taster, I-mutant 3.0, and MuPRO were used. The MODELLER-CABS based hybrid approach was used for protein structure modelling. In silico analysis predicted the p.D658G variant to be deleterious, and it may affect the stability of protein and protein-protein interaction. The findings of this study suggested that the genetic variant p.D658G of the WDR36 gene is a rare genetic cause of POAG in Pakistani patients. The in silico tools predicted the variant p.D658G to be deleterious; however the modelled normal and mutant structure showed no effect on protein structure and function. To further confirm the pathogenic effect of this SNP, in vivo experiments, X-ray Crystallography of the WDR36 protein and population-based studies are needed.

Polyhydramnios associated with rare genetic syndromes: two case reports

BackgroundWe present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to highlight these rare genetic conditions when obstetricians consider differential diagnoses of polyhydramnios in the third trimester.Case presentationPatient 1 is a 34-year-old Asian woman who was diagnosed with polyhydramnios at 28 weeks’ gestation. First trimester testing, fetal anomaly scan, and intrauterine infection screen were normal. Subsequent antenatal ultrasound scans revealed macroglossia, raising the suspicion for Beckwith–Wiedemann syndrome. Chromosomal microarray analysis revealed a female profile with no pathological copy number variants. The patient underwent amnioreduction twice in the pregnancy. The patient presented in preterm labor at 34 weeks’ gestation but elected for an emergency caesarean section. Postnatally, the baby was noted to have a bell-shaped thorax, coat hanger ribs, hypotonia, abdominal distension, and facial dysmorphisms suggestive of Kagami–Ogata syndrome. Patient 2 is a 30-year-old Asian woman who was diagnosed with polyhydramnios at 30 weeks’ gestation. She had a high-risk first trimester screen but declined invasive testing; non-invasive prenatal testing was low risk. Ultrasound examination revealed a macrosomic fetus with grade 1 echogenic bowels but no other abnormalities. Intrauterine infection screen was negative, and there was no sonographic evidence of fetal anemia. She had spontaneous rupture of membranes at 37 + 3 weeks but subsequently delivered by caesarean section in view of pathological cardiotocography. The baby was noted to have inspiratory stridor, hypotonia, low-set ears, and bilateral toe polysyndactyly. Further genetic testing revealed a female profile with a pathogenic variant of the GLI3 gene, confirming a diagnosis of Greig cephalopolysyndactyly syndrome.ConclusionThese cases illustrate the importance of considering rare genetic causes of polyhydramnios in the differential diagnosis, particularly when fetal anomalies are not apparent at the 20-week structural scan. We would like to raise awareness for these rare conditions, as a high index of suspicion enables appropriate counseling, prenatal testing, and timely referral to pediatricians and geneticists. Early identification and diagnosis allow planning of perinatal care and birth in a tertiary center managed by a multidisciplinary team.

Neuroimaging of Parkinson's disease by quantitative susceptibility mapping

Parkinson's disease (PD) is a common neurodegenerative disease, and apart from a few rare genetic causes, its pathogenesis remains largely unclear. Recent scientific interest has been captured by the involvement of iron biochemistry and the disruption of iron homeostasis, particularly within the brain regions specifically affected in PD. The advent of Quantitative Susceptibility Mapping (QSM) has enabled non-invasive quantification of brain iron in vivo by MRI, which has contributed to the understanding of iron-associated pathogenesis and has the potential for the development of iron-based biomarkers in PD. This review elucidates the biochemical underpinnings of brain iron accumulation, details advancements in iron-sensitive MRI technologies, and discusses the role of QSM as a biomarker of iron deposition in PD. Despite considerable progress, several challenges impede its clinical application after a decade of QSM studies. The initiation of multi-site research is warranted for developing robust, interpretable, and disease-specific biomarkers for monitoring PD disease progression.

Clinicopathological Features of Hereditary Nephritis in the Iranian Population: Analysis of a 14-Year Survey in Kidney Biopsies From a Large Referral Center.

Hereditary nephritis (HN), including Alport syndrome (AS) and thin basement membrane nephropathy (TBMN), is a rare genetic cause of hematuria. A definitive diagnosis requires electron microscopy (EM). Therefore, the clinical characteristics of these conditions are less known. This study aimed to determine the percentage and clinicopathological features of HN in patients from a referral center in Iran. We checked kidney biopsy reports from 2007 to 2021 and extracted cases with HN. Fresh specimens of the cases diagnosed in the last two years were stained by immunofluorescence (IF) for collagen type IV alpha chains. EM findings in these cases were re-evaluated and categorized as diffuse glomerular basement membrane (GBM) thinning, definite, and suspicious features of AS. We analyzed 3884 pathology reports of kidney biopsies from 2007 to 2021 and identified 210 patients (5.4%) with HN, with a mean age of 13.78±12.42 years old. Hematuria with proteinuria (53.3%), isolated hematuria (44.2%), and proteinuria with hematuria and increased creatinine (2.5%) were found in these patients. The re-evaluation of EM findings revealed GBM thinning, definite, and suspicious findings of AS in 37.5%, 43.8%, and 18.8% cases, respectively. The most common diagnosis in 32 cases after the IF study was X-linked AS (71.9%), and 6.2% of cases were autosomal recessive AS. TBMN and autosomal dominant AS remained the differential diagnoses in 21.9%. It was found that EM is helpful for the primary diagnosis of patients with definite AS. Immunostaining improves the diagnostic sensitivity for the differentiation of those with suspicious EM findings and determines the inheritance pattern. However, a multidisciplinary approach for a subset of cases is required for the best diagnosis and management.

Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.

FRI092 Rationale And Design Of The Balance Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Olezarsen In Patients With Familial Chylomicronemia Syndrome

Abstract Disclosure: V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Karwatowska-Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. E.S. Stroes: Other; Self; Akcea Therapeutics, Ionis Pharmaceuticals Inc., Amgen Inc, Novo Nordisk, AstraZeneca, Esperion. C. Ballantyne: Speaker; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: None. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. J. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Employee; Self; Ionis Pharmaceuticals Inc. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic cause of severe hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). Currently, there are no approved therapies for the treatment of FCS in the United States, and the absence of lipoprotein lipase (LPL) activity in FCS limits the effectiveness of current treatment options. Olezarsen, a ligand-conjugated antisense oligonucleotide (ASO), inhibits hepatic production of apolipoprotein (apo) C-III, a key regulator of LPL-mediated triglyceride (TG) lipolysis and non-LPL-mediated TG-rich lipoprotein hepatic uptake. In a phase 2 study of non-FCS patients with fasting serum TG levels of 200–500 mg/dL, olezarsen demonstrated reduction in fasting TG levels of up to 60% vs placebo (PBO). The Balance trial (NCT04568434) will evaluate the efficacy and safety of olezarsen as well as the rates of AP in patients with FCS. Methods: Balance is a phase 3, randomized, double-blind, PBO-controlled trial. Key inclusion criteria are genetic confirmation of FCS, fasting TG ≥ 880 mg/dL, and possible history of pancreatitis. Key exclusion criteria include clinically significant abnormalities in medical history such as major surgery within 3 mos of screening and active pancreatitis within 4 wks of screening. Patients will maintain ≤ 20 g daily fat intake and most will receive lipid-lowering medications per local standard of care. Results: Eligible patients (N=66) were enrolled at 29 sites (across 11 countries) and randomized 2:1 to receive one of two doses of olezarsen or PBO over a 53-wk treatment period, followed by post-treatment evaluation or entry into an open-label extension study. Enrollment was monitored to ensure that ≥ 65% of patients had history of pancreatitis within 10 yrs. Reported baseline parameters are preliminary. Of enrolled patients, mean age is 45±13.4 yrs, 58% of the population are female, and mean body mass index is 24.0 kg/m2; 83% had a history of hospitalization for AP, or severe abdominal pain episode, or symptoms suggestive of pancreatitis, with a mean of 2.4 episodes over the last 5 yrs and 5.1 over the last 10 yrs. Median fasting TG level is 2334.5 mg/dL. The primary efficacy endpoint of the study is percent change in fasting TG from baseline (BL) at 6 mos with olezarsen compared to PBO. Secondary endpoints (olezarsen vs PBO) include percent change in fasting TG from BL at 12 mos, achievement of ≥ 40% or ≥ 70% fasting TG reduction at 6 mos, patient proportions ≤ 500 mg/dL or ≤ 750 mg/dL at 6 mos, and adjudicated AP event rates. Exploratory assessments include patient-reported symptoms such as abdominal pain and health-related quality of life. Safety and tolerability assessments include adverse events and laboratory tests. Conclusion: Balance is designed to determine whether the apoC-III ASO olezarsen, added to standard of care, safely reduces TG levels and the rate of AP in patients with FCS. Presentation: Friday, June 16, 2023

Hereditary multiple exostoses caused by a chromosomal inversion removing part of EXT1 gene

BackgroundHereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony protuberances called osteochondromas. Most HME are caused by EXT1 and EXT2 loss of function mutations. Most pathogenic mutations are nonsense followed by missense mutations and deletions.Case presentationHere we report on a patient with a rare and complex genotype resulting in a typical HME phenotype. Initial point mutation screening in EXT1 and EXT2 genes by Sanger sequencing did not reveal any pathogenic variants. The patient along with the healthy parents was subsequently referred for karyotype and array-Comparative Genomic Hybridization (CGH) analyses.Chromosomal analysis revealed two independent de novo apparently balanced rearrangements: a balanced translocation between the long arms of chromosomes 2 and 3 at breakpoints 2q22 and 3q13.2 and a pericentric inversion with breakpoints at 8p23.1q24.1. Both breakpoints were confirmed by Fluorescence In Situ Hybridization (FISH). Subsequently, array-CGH revealed a novel heterozygous deletion within the EXT1 gene at one of the inversion breakpoints, rendering the inversion unbalanced. The mode of inheritance, as well as the size of the deletion were further investigated by Quantitative Real-time PCR (qPCR), defining the deletion as de novo and of 3.1 kb in size, removing exon 10 of EXT1. The inversion in combination with the 8p23.1 deletion most likely abolishes the transcription of EXT1 downstream of exon 10 hence resulting in a truncated protein.ConclusionsThe identification of a rare and novel genetic cause of HME, highlights the importance of additional comprehensive investigation of patients with typical clinical manifestations, even when EXT1 and EXT2 mutation analysis is negative.

Phenotype and imaging features associated with APP duplications

BackgroundAPP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers.MethodsClinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls.ResultsMajor neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia.DiscussionPhenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology.

An inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS. We performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI. Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum. While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality.

PMON33 Non-Syndromic SRY Negative 46 XX Testicular Disorder of Sex Development (DSD): A Rare Cause of Infertility

Abstract Introduction Male infertility can be categorized as endocrine and systemic disorders, primary testicular defects in spermatogenesis, sperm transport disorders and idiopathic male infertility. Chromosomal abnormalities are one of the primary testicular defects. The overall incidence of chromosome abnormalities in infertile men is estimated to be around 5.8%. XX male is a rare sex chromosomal disorder in infertile men. We present case of a young patient with infertility, azoospermia, hypergonadotropic hypogonadism and classical (46, XX) karyotype with negative FISH and SRY gene. Case report: 28-Year-old gentleman was referred to adult endocrinology clinic as part of work up for infertility. Initial work up included 2 semen analyses which were consistent with azoospermia. Examination revealed height 180 cm, weight 77 kg, a body mass index 24 kg/m2, normal phenotypic male without gynecomastia and had normal male pattern hair distribution. Genital examination showed normal male phallus without hypospadias, a hypoplastic scrotum, bilateral firm testes, with no varicocele or hydrocele. Labs were suggestive of compensated primary hypogonadism (FSH 47.9 mIU/ml, LH 20.4 mIU/ml, total testosterone 397.9 ng/dl by LC/MS, free testosterone 15.76 ng/dl by equilibrium dialysis, Inhibin B < 10 pg/ml, and anti-Mullerian hormone 0.390 ng/ml. Given normal testosterone levels, he was not started on testosterone replacement. Karyotype analysis revealed 46 XX and FISH was negative for SRY gene. CT imaging of abdomen and pelvis did not reveal any Mullerian structures, prostrate and seminal vesicles reported as normal. Patient met with a Urologist and was informed that testicular sperm extraction will not be a possibility for him. Patient had a detailed consultation with a geneticist for genetic and family counseling. Chromosome microarray analysis was obtained and was normal. Invitae Disorders of sex development (DSD) panel obtained for genetic sequencing of 53 genes including SOX-9, DHH, WNT4, WT1, was found to be non-diagnostic. Conclusion and Discussion SRY negative 46 XX male is a DSD and a rare genetic cause of male factor infertility, with a discrepancy between genotype and phenotypic sex. In the case presented, genetic work up for potential etiologies has been unrevealing. Further studies are needed to identify the genetic causes of the SRY negative 46 XX male phenotype. Physicians involved in care of these patients should orient with clinical management and prognosis. For Classical 46 XX Males seeking fertility, the current options include invitro-fertilization with donor sperm or adoption only. Testosterone replacement should be considered to correct hypogonadism for physical and sexual well-being. Genetic consultation should be sought in all these cases. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR08-6 A Novel Nonsense Mutation in Delta-Like Non-Canonical Notch Ligand 1 Gene (DLK1) in a French Girl With Central Precocious Puberty

Abstract Background Central precocious puberty (CPP) results from early reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Four monogenic causes of CPP have been described (KISS, KISS1R MKRN3 and DLK1). Rare loss-of-function mutations of DLK1, a maternally imprinted gene located on chromosome 14q32.2, were identified in families with CPP. Both inherited or de novo DLK1 mutations were described in these affected families. Objective To investigate genetic abnormalities in the DLK1 in a French cohort of patients with idiopathic CPP. Patients: Genomic DNA was obtained from 122 patients (99 girls and 23 boys) with sporadic or familial CPP. Automatic sequencing of the coding regions of DLK1 gene (5 exons, using Sanger method) was performed in all cases, including 91 familial and 31 sporadic cases. Results A pathogenic heterozygous variant in the DLK1 gene (c.372C>A p.Cys124Ter (rs749564412) was identified in a girl with sporadic CPP associated with overweight. This nonsense mutation was considered rare (gnomAD total population 1/251,082) and it was located in the third EGF-like repeat domain in the extracellular region. The affected girl had progressive breast development at 4.5 years and accelerated growth velocity. She had breast development Tanner stage 4 at 5.5 years and bone age (BA) was 6 yr. Her height was 114.5 cm and BMI 18.16 (BMI Z-score = 2.48). Basal LH and FSH was 0.6 IU/L and 5.7 IU/L, respectively. GnRH-stimulated LH and FSH peaks were 14 IU/L and 18 IU/L, respectively, with LH: FSH ratio of 0.77. Other hormonal results were normal (estradiol: 11 pg/mL; ACTH: 11 pg/mL; IGF-1: 235 ng/mL; cortisol: 77 ng/mL). Brain MRI was normal. Pelvic ultrasound revealed uterus length: 49 mm, mucosal thickness of 4 mm, ovaries 20 and 25 mm with follicles less than 10 mm. She was treated with a depot GnRH analog (triptorelin). The DLK1 variant was inherited from her asymptomatic father who had a height of 181 cm. Familial history of CPP history was denied. Conclusion DLK1 loss-of-function are rare genetic cause of familial or sporadic CPP. Novel genetic findings in this factor reinforce its role in the physiopathology of the premature HPG axis reactivation and precocious sexual development in humans. Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.

PMON33 Non-Syndromic SRY Negative 46 XX Testicular Disorder of Sex Development (DSD); A rare cause of Infertility

Abstract Introduction Male infertility can be categorized as endocrine and systemic disorders, primary testicular defects in spermatogenesis, sperm transport disorders and idiopathic male infertility. Chromosomal abnormalities are one of the primary testicular defects. The overall incidence of chromosome abnormalities in infertile men is estimated to be around 5.8%. XX male is a rare sex chromosomal disorder in infertile men. We present case of a young patient with infertility, azoospermia, hypergonadotropic hypogonadism and classical (46, XX) karyotype with negative FISH and SRY gene. Case report: 28-Year-old gentleman was referred to adult endocrinology clinic as part of work up for infertility. Initial work up included 2 semen analyses which were consistent with azoospermia. Examination revealed height 180 cm, weight 77 kg, a body mass index 24 kg/m2, normal phenotypic male without gynecomastia and had normal male pattern hair distribution. Genital examination showed normal male phallus without hypospadias, a hypoplastic scrotum, bilateral firm testes, with no varicocele or hydrocele. Labs were suggestive of compensated primary hypogonadism (FSH 47.9 mIU/ml, LH 20.4 mIU/ml, total testosterone 397.9 ng/dl by LC/MS, free testosterone 15.76 ng/dl by equilibrium dialysis, Inhibin B < 10 pg/ml, and anti-Mullerian hormone 0.390 ng/ml. Given normal testosterone levels, he was not started on testosterone replacement. Karyotype analysis revealed 46 XX and FISH was negative for SRY gene. CT imaging of abdomen and pelvis did not reveal any Mullerian structures, prostrate and seminal vesicles reported as normal. Patient met with a Urologist and was informed that testicular sperm extraction will not be a possibility for him. Patient had a detailed consultation with a geneticist for genetic and family counseling. Chromosome microarray analysis was obtained and was normal. Invitae Disorders of sex development (DSD) panel obtained for genetic sequencing of 53 genes including SOX-9, DHH, WNT4, WT1, was found to be non-diagnostic. Conclusion and Discussion SRY negative 46 XX male is a DSD and a rare genetic cause of male factor infertility, with a discrepancy between genotype and phenotypic sex. In the case presented, genetic work up for potential etiologies has been unrevealing. Further studies are needed to identify the genetic causes of the SRY negative 46 XX male phenotype. Physicians involved in care of these patients should orient with clinical management and prognosis. For Classical 46 XX Males seeking fertility, the current options include invitro-fertilization with donor sperm or adoption only. Testosterone replacement should be considered to correct hypogonadism for physical and sexual well-being. Genetic consultation should be sought in all these cases. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Early subclinical systolic dysfunction detected by two-dimensional speckle tracking systolic strain in patients with hereditary TTR amyloidosis

Abstract Background Transthyretin Amyloidosis (ATTR) is a rare genetic cause of potentially fatal infiltrative cardiomyopathy. This is the commonest form of inherited restrictive cardiomyopathy. The Transthyretin (TTR) gene is located on chromosome 18q12.1 with autosomal dominant inheritance and variable penetrance. The availability of genetic testing has identified a carrier population without cardiac amyloidosis. 2-dimensional speckle-tracking echocardiography (2D-STE) has been the mainstay of screening and disease surveillance. However, utility of echocardiography for the comprehensive analysis of biventricular strains are not reported in a carrier population without cardiac amyloidosis. We sought to study the global and regional indices of biventricular strain in genotyped cases of ATTR. Purpose To assess whether individuals with a family history of TTR amyloidosis associated with a positive genetic study for transthyretin mutation can develop cardiac abnormalities even before the clinical manifestation of the disease, which may early clarify the cardiovascular risk of this pathology. Methods Patients with genotype TTR positive (TTR+) without cardiovascular symptoms were identified and matched with healthy controls. All patients underwent a full echocardiogram using a standardized protocol: 2D dimensions, tissue Doppler (TDI) and 2D-STE parameters were analyzed. Data are reported as means with standard deviation (±SD) or median with interquartile range [IQR]. Statistics performed were parametric and non-parametric tests, with a p value of <0.05 accepted as significant. In order to identify variables that could be associated with patients TTR genotype positive, an analysis of multiple logistic regression was proposed. Results 31 individuals in TTR+ and 34 controls were studied. Demographic and echocardiography parameters characteristics are detailed in Table. There was no significant difference in chamber dimensions, length, or ejection fraction between groups. Compared with controls, left ventricular (LV) wall thickness and mass index was higher in TTR+ (Table). Average E/e' tended to be higher in TTR+ (table). LV global circumferential and longitudinal strain were significantly lower in TTR+ (−28±4% vs. −21±4%, −25±2% vs. −19±3%, p<0.001 for all). Bull's eyes of the peak Longitudinal Strain are showed in Figure 1. RV strain was also lower in the TTR+ group (−25±5% vs. −18±4%, p<0.005). Additionally, there was a significant reduced in longitudinal strain basal, mid, and apical in TTR+ group (Table). The predictors of positive genetic testing were global longitudinal strain (adjusted odds ratio [95% CI], 2.46 [1.30–4.62]; p=0.005) and average E/e' (2.04; [1.09–3.91]; p=0.025). Conclusion Global and regional biventricular strain is lower in individuals with genetically proven TTR prior to development of cardiac amyloidosis. The impact of these variables as a component of a screening. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Conselho Nacional de Desenvolvimento Científico e Tecnolόgico (CNPq)

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program

Clinical-genetic findings in a group of subjects with macular dystrophies due to mutations in rare inherited retinopathy genes.

To describe the results of clinical and molecular analyses in a group of patients suffering from inherited macular dystrophies, in which next-generation sequencing (NGS) efficiently detected rare causative mutations. A total of eight unrelated Mexican subjects with a clinical and multimodal imaging diagnosis of macular dystrophy were included. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field tests, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed by means of whole exome sequencing with subsequent Sanger sequencing validation of causal variants. All patients exhibited a predominantly macular or cone-dominant disease. Patients' ages ranged from 12 to 60years. Three cases had mutations in genes associated with autosomal dominant inheritance (UNC119 and PRPH2) while the remaining five cases had mutations in genes associated with autosomal recessive inheritance (CNGA3, POC1B, BEST1, CYP2U1, and PROM1). Of the total of 11 different pathogenic alleles identified, three were previously unreported disease-causing variants. Macular dystrophies can be caused by defects in genes that are not routinely analyzed or not included in NGS gene panels. In this group of patients, whole exome sequencing efficiently detected rare genetic causes of hereditary maculopathies, and our findings contribute to expanding the current knowledge of the clinical and mutational spectrum associated with these disorders.