Autosomal Recessive Pattern Of Inheritance Research Articles

Limbic System Associated Membrane Protein Mutation in an Iranian Family Diagnosed with Ménière's Disease.

Ménière's disease (MD) is a common inner ear disorder which is characterized by recurrent attacks of vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and a sense of fullness in the affected ear. MD is a complex disorder; although six genes have been linked to familial autosomal dominant form of the disease, in many cases, the exact genetic etiology remains elusive. To elucidate the genetic causes of MD in an Iranian family, we performed exome sequencing on all members of the family: consanguineous parents and four children (two affected and two unaffected). Variant filtering was completed using a customized workflow keeping variants based on segregation with MD in autosomal recessive (AR) inheritance pattern, minor allele frequency (MAF), and in-silico prediction of pathogenicity. Analysis revealed that in this family, 970 variants co-segregated with MD in AR pattern, out of which eight variants (one intergenic, four intronic, and three exonic) were extremely rare. The exonic variants included a synonymous substitution in USP3 gene, an in-frame deletion in ZBED2 gene, and a rare, highly conserved deleterious missense alteration in LSAMP gene. The phenotype observed in the proband described here, i.e. vertigo, poor sense of smell, tinnitus, and borderline hearing ability, may originate from aberrant changes in the cerebellum and limbic system due to a deleterious mutation in the LSAMP gene; hence, LSAMP mutation is a possible candidate for the etiology of MD in this family.

Result of carrier screening for spinal muscular atrophy among 3049 reproductive-age individuals from Yunnan region

To perform carrier screening for spinal muscular atrophy (SMA) among 3049 reproductive-age individuals from Yunnan region and determine the copy number of survival motor neuron (SMN) gene and carrier frequencies. Multiplex ligation-dependent probe amplification (MLPA) was used to determine the copy number of exon 7 of SMN1 and SMN2 genes and identify those with a single copy of SMN1 gene. Prenatal diagnosis was performed for couples whom were both found to be SMA carriers. In total 62 SMA carriers were identified among the 3049 subjects, which yielded a carrier frequency of 1 in 49 (2.03%). No statistical difference was found in the carrier frequency between males and females (1.91% vs. 2.30%, P>0.05). Respectively, 1.3% (41/3049) and 0.69% (21/3049) of the carriers were caused by heterozygous deletion and conversion of the SMN1 gene. The average copy number for SMN1 alleles was 1.99. Two couples were found to be both as SMA carriers, for whom the birth of an affected fetus was avoided by prenatal diagnosis. No difference was found in the carrier frequency of SMA-related mutations between the two genders in Yunnan region, which was in keeping to an autosomal recessive inheritance pattern. Determination of the carrier frequency for SMA and SMN gene variants may provide a basis for genetic counseling and prenatal diagnosis for the disease.

Human leukocyte antigen association with familial steroid-sensitive nephrotic syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics may play a role in the disease. Human leucocyte antigen (HLA) alleles have been associated with SSNS. We present genetic findings in nine families (44 participants), each with at least two affected siblings. A total of 19 patients were affected with familial SSNS. Six of nine families showed linkage to markers on chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. Interestingly, we also found linkage of disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score Z = 3.02.Conclusion: Our findings confirm the linkage of HLA markers on chromosome 6, which strengthens the association of HLA alleles in SSNS. What is Known: • Human leukocyte antigen (HLA) alleles have been associated with idiopathic steroid-sensitive nephrotic syndrome (SSNS). Only few studies have investigated the association between HLA alleles and familial SSNS. What is New: • We present evidence of linkage of familial SSNS to chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. We also found linkage of the disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score of Z = 3.02 following autosomal recessive inheritance pattern.

SAT-436 CLINICAL AND GENETIC CHARACTERISTICS OF AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) PATIENTS FROM OMAN AND PKHD1 FOUNDER MUTATIONS

The Omani population has a high prevalence of rare genetic disorders, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in the country. We aimed to describe the clinical and genetic profile of ARPKD patients from Oman. A group of 75 patients and relatives (40 males and 35 females) from apparently 33 unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018, were studied. This included 41 patients with a clinical diagnosis of ARPKD, their parents (n=24) and siblings or relatives (n=10). Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing. A clinical diagnosis was made in 5 patients prenatally, 24 were diagnosed during the infancy period (0-1 year), nine during early childhood (2-8 years) and 3 at later ages (9-13 years). The main clinical features of patients included hypertension, hepatic fibrosis and splenomegaly. 25 patients had documented chronic renal failure at a median age of 3 years. 24 out of 33 families had a family history suggesting an autosomal recessive pattern of inheritance, and there was known consanguinity in 22 families (67%). A molecular genetic diagnosis of ARPKD with biallelic PKHD1 mutations was confirmed in 30 families (n= 38 patients), giving a detection rate of 91%. Three families remained genetically unsolved. In total, only four different PKHD1 missense pathogenic mutations were identified: c.107C>T; (Thr36Met), c.406A>G; (Thr136Ala), c.4870C>T; (Arg1624Trp) and c.9370C>T; (His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G; (Thr136Ala) is a novel missense mutation that was detected homozygously in one family and heterozygously with c.107C>T; (Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families. All four PKHD1 mutations were detected in patients from all governorates of the country except, Musandam, Al Wusta and Dhofar. Molecular genetic screening of suspected ARPKD cases produces a highly yield of genetic diagnosis. The four PKHD1 missense mutations may suggest common founder alleles in Omani population and allow cost effective targeted PCR analysis of these specific alleles to be a useful diagnostic tool.

Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis

BackgroundKaryomegalic interstitial nephritis (KIN) is a rare hereditary cause of chronic kidney disease. It typically causes progressive renal impairment with haemoproteinuria requiring renal replacement therapy before 50 years of age. It has been associated with mutations in the Fanconi anaemia-associated nuclease 1 (FAN1) gene and has an autosomal recessive pattern of inheritance. Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is the third most common cause of amyloid nephropathy presenting with chronic kidney disease and variable proteinuria. We report a novel mutation in the FAN1 gene causing KIN and to our knowledge, the first case of concurrent KIN and ALECT.Case presentationWe describe the case of 44 year old Pakistani woman, presenting with stage four non-proteinuric chronic kidney disease, and a brother on dialysis. Renal biopsy demonstrated KIN and concurrent ALECT2. Genetic sequencing identified a novel FAN1 mutation as the cause of her KIN and she is being managed conservatively for chronic kidney disease. Her brother also had KIN with no evidence of amyloidosis and is being worked up for kidney transplantation.ConclusionThis case highlights two rare causes of chronic kidney disease considered underdiagnosed in the wider population due to their lack of proteinuria, and may contribute to the cohort of patients reaching end stage renal disease without a renal biopsy. We report a novel mutation of the FAN1 gene causing KIN, and report the first case of concurrent KIN and ALECT2. This case highlights the importance of renal biopsy in chronic kidney disease of unclear aetiology which has resulted in a diagnosis with implications for kidney transplantation and family planning.

An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18)

Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease

BackgroundSensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects.ResultsTwo male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood.ConclusionThe finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.

Family Trimethylaminury Associated with Hereditary Angioedema

There are patients who complain of giving off a fishy smell through the skin and sweat, which can be a cause of stress in which the doctor often fails to accept this situation, or even the patient or his family members are ashamed of communicate these symptoms, causing their isolation. Trimethylaminuria, also called fish smell syndrome or fish smell syndrome, is a very rare metabolic disorder that presents an autosomal recessive inheritance pattern, causing an alteration in the function of the enzyme flavinmonooxygenase 3 (FMO3 ). On the other hand, the presence of alterations in the inflammatory chain that governs the complement cascade is responsible for clinical situations that require an accurate diagnosis, such as Hereditary Angioedema, since their evolution can be the origin of clinical complications, serious times We present a case of family Trimethylaminuria in which the affected are two brothers of 2 and 6 years, and whose diagnosis could be obtained since the male patient presented an outbreak of inflammation of the face finally identified as Hereditary Angioedema.

Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland.

The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.

Harlequin ichthyosis: a rare genetic dermatosis in Nigeria

Harlequin ichthyosis (HI) is a rare genetic skin disorder characterized by dry, thickened, scaly, fish-like skin with an autosomal recessive inheritance pattern. It is the severest form of ichthyosis and is associated with poor survival. We report a case of HI that presented to our facility and highlight the challenges associated with the management of this condition in our environment.

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies.

The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.

Association of the carriage of <i>BRD2</i> rs206787 and rs516535 and <i>GJD2</i> rs3743123 polymorphisms with juvenile myoclonic epilepsy in Caucasian patients of Siberia

In recent years, the genetics of juvenile myoclonic epilepsy (JME) has been actively studied; the association of JME with the carriage of polymorphic allelic variants of the BRD2 (EJM3 locus) and GJD2 (EJM2 locus) genes has been established. Objective: to establish risk factors for JME in terms of a genetic predisposition; specifically, polymorphic allelic variants rs206787 and rs516535 in the BRD2 gene and rs3743123 in the GJD2 gene. Patients and methods: Examinations were made in 79 patients with JME and in 150 healthy volunteers, who were Caucasian and resided in the Siberian Federal District (SFD) and underwent determination of the carriage of single nucleotide polymorphisms (SNPs) rs206787 and rs516535 in the BRD2 gene and rs3743123 in the GJD2 gene by real-time polymerase chain reaction. Results and discussion. In 2003, American scientists from New York showed that the alleles associated with the development of JME with an autosomal recessive inheritance pattern might be located in the BRD2 gene. Patients with JME are assumed to have an autosomal dominant inheritance pattern of mutations in the BRD2 gene. British scientists revealed that different populations were found to have an association of SNP rs3918149 and no relationship of BRD2 rs206787 to the development of JME in Caucasians, as well as ascertained local linkage disequilibrium in the BRD2 gene. Our investigation has established complete linkage disequilibrium between the loci in patients with JME and in healthy individuals and no association of the carriage of SNPs rs206787 and rs516535 in the BRD2 gene with the development of JME in the patients residing in the SFD (p >0.05). German scientists studied the impact of SNP in the BRD2 gene on a predisposition to a photoparoxysmal response in patients with JME/genetic generalized epilepsy. Our investigation has indicated the association of the carriage of TT/TT haplotype for SNP rs206787 and rs516535 in the BRD2 gene with a photoparoxysmal response in patients with JME (odds ratio (OR), 3.6; 95% confidence interval (CI), 1.37–9.48; p=0.02). We have confirmed that in the studied sample, the carriage of the T allele in the GJD2 gene (rs3743123) in the homozygous form is associated with the development of JME in Caucasian patients residing in the SFD and is a risk factor for JME (OR, 2.66; 95% CI, 1.24–5.74; p=0.04). The clinically significant association of this SNP in the GJD2 gene with the development of JME had been also previously demonstrated in two independent studies conducted in the European populations in the UK and Germany. There is a rise in the proportion of homozygotes in JME patients versus the control group, suggesting that the 588T allele under consideration increases the risk for JME in the homozygous state in the autosomal recessive inheritance pattern. Conclusion. The findings suggest that it is necessary to genotype Caucasian patients with JME, who reside in Siberia, for determination of the carriage of the TT/TT haplotype in terms of the investigated SNPs in the BRD2 gene (EJM 3 locus) and the carriage the T allele (rs3743123) in the GJD2 gene via a personalized approach to predicting the course of JME, as well as for identification of persons at risk for JME in the families having a history of this disease.

Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare inborn lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene with an autosomal recessive pattern of inheritance. To date, only 19 CTX patients from 16 families have been reported in the Chinese population.ResultsThree novel likely pathogenic mutations (c.368_374delCCAGTAC, c.389 T > A and c.571C > T) and 7 previously reported pathogenic mutations (c.379C > T, c.435G > T, c.1016C > T, c.1214G > A, c.1263 + 1G > A, c.1420C > T and c.1435C > T) were identified. In addition, we summarized the genotypes and phenotypes of reported Chinese CTX patients. The most predominant mutations in CYP27A1 were c.410G > A and c.379C > T, and the most common clinical manifestations were pyramidal signs, xanthomatosis, cerebellar ataxia, and cognitive impairment.ConclusionOur study broadens the genetic and clinical spectrum of CTX and provides insightful information to help better diagnose and understand the disease.

Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines

BackgroundMandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24.MethodsIn 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85–100% of all MADB patients and minor criteria as those present in 70–84% of patients.ResultsAll the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria.ConclusionsWe report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

Pyruvate Kinase Deficiency Cases Mimicking Congenital Dyserythropoietic Anemia

Introduction Pyruvate kinase (PK) deficiency is the most common glycolytic pathway defect that leads to hereditary hemolytic anemia with autosomal recessive inheritance pattern, which may present with severe hemolysis in the neonatal period, frequent blood transfusion requirement during infancy or with milder course of anemia. The prevalence reported among the Caucasians is 51 per million. Herein we present two cases of PK deficiency who were clinically and morphologically mimicking congenital dyserythropoietic anemia (CDA) at presentation and were diagnosed molecularly. Case 1 A three-year-old male patient was admitted with jaundice. Personal history revealed that he was born prematurely from a non-consanguineous family, and he did not need phototherapy at neonatal period. By the third month, he received first erythrocyte transfusion; then he needed transfusions every month. Strikingly, transfusion requirements increased in febrile episodes. Physical examination at admission revealed jaundice and splenomegaly. Complete blood count showed hemoglobin (Hb) 7.2 g/dL, mean corpuscular volume (MCV) 86.1 fL, mean corpuscular hemoglobin (MCH) 27.3 pg, mean corpuscular hemoglobin concentration (MCHC) 31.7 pg, and reticulocytes 12.3%. A blood film examination showed macrocytosis, hypochromia, anisocytosis, and rare spherocytes. Hemoglobin electrophoresis was normal, and direct Coombs' test was negative. The PK enzyme level was ignored since the patient was regularly transfused. Bone marrow aspiration showed erythroid hyperactivity and severe megaloblastic changes with double and multi-nucleated erythroid precursors suggestive for CDA. However, no genetic mutation detected concerning CDA (C15orf41, F8, F9, KLF1, CDAN1, VWF, SEC23B, GATA1, G6IBA genes). After negative molecular testing for CDA, sequencing of the PK-LR gene revealed the presence of a homozygous c.1151C> T mutation. Case 2 A three-month-old male patient presented with pallor and jaundice. Personal history revealed that he was born at term from a non-consanguineous family, and he required phototherapy and exchange transfusion due to icterus and anemia at the neonatal period. He needed erythrocyte transfusions during follow-up. Hemogram revealed Hb 6.7 g/dL, MCV 81.2 fL, MCH 25.2 pg, MCHC 31.1 pg, and reticulocytes 2.6%. Blood film examination showed polychromasia, rare spherocytes, and acanthocytes. Direct Coombs' test and Parvovirus B19 PCR analysis were negative. Bone marrow aspiration showed erythroid hyperactivity along with double and multi-nucleated erythroid precursors, which suggested CDA. However, no genetic mutation detected concerning CDA (SEC23B, CDAN1). The PK enzyme level was normal, which was 2 ½ months after the last transfusion. Finally, the molecular analysis of the PK-LR gene revealed the presence of a novel homozygous c.880G>A mutation. The mutation predicted as possibly damaging by in Silico analysis. Discussion The diagnostic approach to transfusion-dependent hereditary hemolytic anemia could be challenging related to false normal erythrocyte enzyme studies and osmotic fragility tests in previously transfused patients. It was reported that PK deficiency cases with inappropriately low reticulocytes might mimic CDA, which was discerned in cases where NGS performed for CDA but revealed PK-LR mutation. PK deficiency may lead to ineffective erythropoiesis due to erythrocyte ATP depletion, as well as CDA-like morphological findings (Cases 1 and 2) and low reticulocyte counts (Case 2). We suggest that in cases where CDA is suspected, PK deficiency should be considered in the differential diagnosis. Furthermore, instead of the PK enzyme level in patients with regular transfusions, PK-LR genetic analysis would be appropriate. Disclosures No relevant conflicts of interest to declare.

Platelet Function Disorder Is More Common Than Von Willebrand Disease in Women with Inherited Bleeding Disorders: Report from a Public Sector University in Pakistan

Abstract Introduction: Inherited bleeding disorders are an important cause of menorrhagia. Aim: To determine the prevalence of inherited bleeding disorders in women with menorrhagia in the absence of systemic and pelvic pathologies. Methods: The study period was from March 2013 to September 2018. It was carried out at the Department of Obstetrics & Gynecology, Unit II, Dow Medical College and Ruth Pfau KM Civil Hospital in Karachi. The laboratory investigations were carried out partly at Dow Diagnostic Research Laboratory and mainly at the National Institute of Blood Disease & Bone Marrow Transplant. Included in the study were young girls and women who presented with menorrhagia at menarche or in the later years of reproduction, with normal bimanual pelvic examination and pelvic ultrasound results. Results: Approximately 200 women with a mean menstrual cycle duration of 9.3+ 3.5 days were included. The mean age of the included patients was 32 years. Married women's partners were cousins in 50% of the women, while unmarried girls' parents were cousins in all cases. Platelet aggregation defect was presented in 33 (16.6%) women, von Willebrand disease in 26 (13.1%) women, factor IX deficiency in 20 (10%) women, combined defects in 29 (14.6%) women, and factor VII and VIII deficiencies in 4 and 11 (2%, 5.5%) women, respectively. Isolated defect with ADP, epinephrine, and collagen were decreased in 35 (17.6%), 41 (20%), and 33 (16%) women, respectively. Conclusion: Inherited bleeding disorders were a common cause of menorrhagia in our population. Consanguinity was frequently seen in these subjects. Except for some forms of VWD, all other disorders have an autosomal recessive inheritance pattern. After excluding gynecological and medical causes, a work up for inherited bleeding disorders should be advised. Keywords: menorrhagia, platelet function disorder, inherited bleeding disorders, Pakistan. Disclosures No relevant conflicts of interest to declare.

Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.

Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed “non-odonto”) (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL “c.1559delT” mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP.

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

PurposeTo investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. MethodsWe assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. ResultsThe proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p<0.0001). ConclusionWe propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

TRPM1 Mutations are the Most Common Cause of Autosomal Recessive Congenital Stationary Night Blindness (CSNB) in the Palestinian and Israeli Populations

Precise genetic and phenotypic characterization of congenital stationary night blindness (CSNB) patients is needed for future therapeutic interventions. The aim of this study was to estimate the prevalence of CSNB in our populations and to study clinical and genetic aspects of the autosomal recessive (AR) form of CSNB. This is a retrospective cohort study of Palestinian and Israeli CSNB patients harboring mutations in TRPM1 underwent comprehensive ocular examination. Genetic analysis was performed using homozygosity mapping and sequencing. 161 patients (from 76 families) were recruited for this study, leading to a prevalence of 1:6210 in the vicinity of Jerusalem, much higher than the worldwide prevalence. 61% of the families were consanguineous with AR inheritance pattern. Biallelic pathogenic TRPM1 mutations were identified in 36 families (72 patients). Two founder mutations explain the vast majority of cases: a nonsense mutation c.880A>T (p.Lys294*) identified in 22 Palestinian families and a large genomic deletion (36,445 bp) encompassing exons 2–7 of TRPM1 present in 13 Ashkenazi Jewish families. Most patients were myopic (with mean BCVA of 0.40 LogMAR) and all had absent rod responses in full field electroretinography. To the best of our knowledge, this is the largest report of a clinical and genetic analysis of patients affected with CSNB due to TRPM1 mutations.

Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach.

Allgrove syndrome or triple A (3A) syndrome is a multisystem disorder which classically involves the triad of esophageal achalasia, alacrima, and adrenal insufficiency due to adrenocorticotropin hormone insensitivity. It follows an autosomal recessive pattern of inheritance and is associated with mutations in the AAAS (achalasia–addisonianism–alacrima syndrome) gene. Since its first description in 1978, the knowledge on clinical and genetic characteristics has been expanding; however, the current literature is limited to case reports and case reviews. Early recognition of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of kin. The coordination of care for these patients requires a multidisciplinary team of specialists, including endocrinologists, neurologists, gastroenterologists, ophthalmologists, developmental specialists, dentists, geneticists, and surgeons. In this review, we aim to summarize the current recommendations for the diagnosis, management, and follow-up of patients with 3A syndrome.