Evidence For Autosomal Recessive Inheritance Research Articles

Pathogenic variant c.35delG of the GJB2 gene associated with nonsyndromic prelingual deafness

Introduction: the pathogenic variant c.35delG of the GJB2 gene is the most frequently observed in all populations, associated with nonsyndromic autosomal recessive prelingual prelingual sensorineural deafness, since 2001 is available in the National Network of Medical Genetics the study of this mutation. Objective: to describe the presence of the pathogenic variant c.35delG of the GJB2 gene associated with nonsyndromic prelingual deafness, with evidence of autosomal recessive inheritance. Methods: a descriptive cross-sectional study was carried out on 379 cases registered with isolated prelingual hearing loss between 2001 and 2023; for the identification of the c.35delG mutation, the polymerase chain reaction technique was used, with enzymatic digestion, and its genotype and frequency were described. Results: the pathogenic variant c.35delG of the GJB2 gene was found in 121 of those studied (31,91 %), 59 in homozygosis and 62 in heterozygosis. The allele frequency found among the positive cases was 0,743. Conclusion: the pathogenic variant c.35delG in individuals with nonsyndromic prelingual deafness of possible autosomal recessive inheritance is found in a high proportion

Mutations in MYO9B are associated with Charcot-Marie-Tooth disease type 2 neuropathies and isolated optic atrophy.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders caused by mutations in at least 100 genes. However, approximately 60% of cases with axonal neuropathies (CMT2) still remain without a genetic diagnosis. We aimed at identifying novel disease genes responsible for CMT2. We performed whole exome sequencing and targeted next generation sequencing panel analyses on a cohort of CMT2 families with evidence for autosomal recessive inheritance. We also performed functional studies to explore the pathogenetic role of selected variants. We identified rare, recessive variants in the MYO9B (myosin IX) gene in two families with CMT2. MYO9B has not yet been associated with a human disease. MYO9B is an unconventional single-headed processive myosin motor protein with signaling properties, and, consistent with this, our results indicate that a variant occurring in the MYO9B motor domain impairs protein expression level and motor activity. Interestingly, a Myo9b-null mouse has degenerating axons in sciatic nerves and optic nerves, indicating that MYO9B plays an essential role in both peripheral nervous system and central nervous system axons, respectively. The degeneration observed in the optic nerve prompted us to screen for MYO9B mutations in a cohort of patients with optic atrophy (OA). Consistent with this, we found compound heterozygous variants in one case with isolated OA. Novel or very rare variants in MYO9B are associated with CMT2 and isolated OA.

Expanding the spectrum of genes responsible for hereditary motor neuropathies

BackgroundInherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%–70% of cases with...

Early Onset Parkinson\u2019s Disease in a family of Moroccan origin caused by a p.A217D mutation in PINK1: a case report

BackgroundBi-allelic mutations in the genes Parkin (PARK2), PINK1 (PARK6) and DJ-1 (PARK7) are established causes of autosomal recessive early-onset Parkinson’s Disease (EOPD). PINK1 mutations are the second commonest cause of EOPD. Specific mutations may be relatively common in certain populations because of a founder effect. Homozygous p.A217D PINK1 mutations were previously shown to cause EOPD in a large Sudanese kindred.Case presentationHere we report the segregation of homozygous PINK1 p.A217D mutations in a family originating in Morocco with a history of parental consanguinity. From the clinical information available for the index case, the phenotype of mild, slowly-progressive Parkinsonism is consistent with previous reports of p.A217D disease and of PINK1 disease phenotype more generally. The reported features of early prominent lower-limb symptoms and gait disturbance with asymmetrical onset are more frequent among PINK1 disease cases.ConclusionsTogether, reports of p.A217D in families of Moroccan and Sudanese origin suggest that p.A217D is a North African mutation due to a founder effect. Wider genetic analyses of EOPD in North Africa would be useful to estimate the prevalence of Parkinsonism caused by PINK1 p.A217D. In the absence of bi-allelic Parkin mutations, PINK1 mutations should be considered in cases with evidence of autosomal recessive inheritance of EOPD and presentation of atypical features such as early lower-limb symptoms and gait disturbance with asymmetrical onset, which appear to be common in Mendelian EOPD.

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

Population Based Nationwide Study of Hypospadias in Sweden, 1973 to 2009: Incidence and Risk Factors

We studied the incidence of hypospadias in Sweden during a 40-year period to determine if changes were associated with known risk factors. We analyzed prospective data from nationwide health care and demographic registers collected for all males (1,948,591 total) born in Sweden between 1973 and 2009. The incidence of hypospadias per 1,000 live-born boys was calculated as number of cases divided by total number of births yearly. The association between hypospadias and risk factors was estimated using logistic regression, expressed as odds ratios. The nationwide incidence of boys diagnosed with hypospadias was approximately 4.5 per 1,000 live-born boys until 1990, increasing to 8 per 1,000 boys during the following decade. Mild and severe phenotypes comprised the increase. Boys born small for gestational age (OR 4.34), as a twin (OR 1.8), as a result of in vitro fertilization (OR 1.15), or with parents from Asia (OR 1.45) or continental Europe (OR 1.41) were at increased risk for hypospadias. Multivariate analyses revealed that changes in risk factors did not explain the increased incidence. However, a systematic change in the classification of the diagnosis in registers could not be ruled out. This nationwide study demonstrates an increased incidence of hypospadias diagnoses in Sweden from 1990 to 1999 that is not attributable to previously known risk factors. The increase includes mild and severe phenotypes, suggesting that shifts in the diagnostic criteria are not the underlying cause.

Osteogenesis Imperfecta, an Ever-Expanding Conundrum

Osteogenesis imperfecta (OI), or brittle bone disease, a rare heritable connective tissue disorder, was described more than a century ago. Its hallmark, bone fragility, may cause frequent fractures, spine and limb deformities, and chronic pain. Another characteristic of the OI syndrome is its wide spectrum of clinical severity, from the very mild to the lethal. Over the years, there have been several attempts at classifying the various forms of OI either by number or by degrees of severity (reviewed in Glorieux and Rowe). All such efforts have only been partially successful because, except for the extremes of the spectrum, clinical types are overlapping. Furthermore, it has been oftentimes observed that within the same family, affected subjects show a wide variation in clinical presentations. This variability in phenotype severity is matched by an ever‐ expanding genotypic variability. OI is in most cases associated with mutations in COL1A1 and COL1A2, the genes encoding type I collagen, the main component of the bone matrix. Detailed analysis of the large number of identified mutations allowed for two main groups to be delineated. The first one corresponds to mutations leading to haploinsufficiency and overall to a mild phenotype. The second group includes mutations that cause structural abnormalities in the collagen molecule compromising the organization of the bone matrix. Associated phenotypes are usually moderate to severe or, rarely, lethal. All such mutations are transmitted as autosomal dominant traits. However, in a small number (less than 10%) of OI cases, no such association could be established, and inmost of them there was evidence for autosomal recessive inheritance. In the first reported cases from a population isolate, mutations were identified in CRTAP, the gene encoding a cartilage associated protein part of the prolyl 3‐hydroxylation complex involved in the processing of the type I collagen triple helix. Subsequently, mutations were found that affected the other two subunits of the complex, prolyl 3‐hydroxylase 1 and cyclophylin B, as well as chaperones encoded by SERPINH1 and FKBP10 (reviewed in Forlino and colleagues). Thus, up to that point all abnormalities could be linked to the synthesis, secretion, processing, and matrix integration of the type I collagen molecule. Recently, other forms, where no abnormalities related to collagen type I could be elicited, were identified by detailed analysis of undecalcified bone sections obtained from iliac crest biopsies. Pathophysiologic aspects of two such entities are discussed in this issue. The first one, type V OI, was described 13 years ago. Unlike the other “new” forms of OI, it is transmitted as an autosomal dominant trait. Besides bone fragility, its main characteristics include short stature, ossification of the interosseous membrane of the forearm often leading to dislocation/subluxation of the proximal radial head, presence of radiodense bands under the growth plates, and the frequent development of hyperplastic calluses after fractures or corrective surgery. Its unique defining feature is, however, found on bone sections as a loss of the birefringent aspect of the matrix under polarized light illumination. It rather exhibits ameshlike appearance not observed in any other bone disease. Last year, two groups simultaneously reported the association of type V OI with a single identical mutation (c.‐14C> T) in the untranslated region of IFITM5. It introduces a new initiation codon that adds five residues at the N‐terminus of the gene product, an osteoblast‐specific transmembrane protein, BRIL. The findings were rapidly corroborated in a third publication, which added 42 patients to the 21 from the initial reports. Remarkably, all subjects carry the exact same mutation despite a wide variability in its phenotypic expression. Shapiro and colleagues further document this fascinating observation in an additional 17 patients. BRIL was discovered as part of a high‐throughput screen for cDNAs encoding secreted and membrane proteins in osteoblastic cells. BRIL is part of an evolutionary conserved family of so‐ called interferon‐inducible transmembrane (IFITM) proteins for which there are at least four closely related members in the human (IFITM1, 2, 3, and 10) and two others in the mouse (IFITM6 and 7). The inclusion of BRIL as part of this family is based on genomic and protein structure considerations. BRIL, IFITM1, 2, and 3 are all clustered within 25 kb on chromosome 11; they all possess a similar gene architecture comprising two small coding

Elsahy–Waters syndrome: Evidence for autosomal recessive inheritance

Elsahy-Waters or branchioskeletogenital syndrome is a rare MCA/MR syndrome characterized by moderate mental retardation, hypospadias and characteristic craniofacial morphology, which includes brachycephaly, facial asymmetry, exotropia, hypertelorism/telechantus, broad nose, concave nasal ridge, underdeveloped midface, prognathism, and radicular dentin dysplasia. Here we report on a 44-year-old woman and her 45-year-old brother, born to consanguineous parents, who show a striking resemblance to the earlier described patients. The hitherto reported patients were male and in one pedigree parents were consanguineous. The present report of an affected woman and her brother, born to consanguineous parents, supports autosomal recessive inheritance of this condition. We provide a short review of all previously reported patients with Elsahy-Waters syndrome and related entities.

Homozygous LMNA mutation R527C in atypical Hutchinson–Gilford progeria syndrome: evidence for autosomal recessive inheritance

To describe two Chinese siblings of atypical Hutchinson-Gilford progeria syndrome (HGPS), with genetic diagnosis and special clinical manifestation. We screened the LMNA gene in four members of a consanguineous family, in which two children were suffering from atypical HGPS. Besides general HGPS features, such as growth retardation and characteristic appearance, special clinical phenotypes including disorders of digestive system and severe skeletal damages were observed. Homozygous mutation 1579C>T, which predicts R527C, was identified in the exon 9 of LMNA among the affected siblings. Heterozygous carrier status 1579C>T was detected in both of the asymptomatic parents. Homozygous mutation R527C in LMNA yields atypical HGPS, and it suggests an autosomal recessive inheritance in this family.

Duchenne like muscular dystrophy in two sisters: evidence for autosomal recessive inheritance

Duchenne like muscular dystrophy in two sisters: evidence for autosomal recessive inheritance

Sudden death in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type

The spondylo-meta-epiphyseal dysplasias are an expanding group of skeletal dysplasias with specific features differentiating each subtype. We review the precocious carpal mineralization, unique metacarpal shape, triangular distal phalanges and mushroom cloud-shaped proximal phalanges present at an early age in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED SL-AC) and report two patients with clinical and radiographic features consistent with SMED SL-AC, who died suddenly because of spinal cord compression. The patients presented are female siblings, providing further evidence for autosomal recessive inheritance. Cervical cord compression is found in half of reported patients and is the major cause of mortality. SMED SL-AC should be added to the list of genetic causes of sudden death. Radiological features in the hand may be used in the first few years of life to support an early diagnosis and thus allow for prevention of premature demise.

The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew‐Wood syndrome): Report of eight cases including a living child and further evidence for autosomal recessive inheritance

The combination of pulmonary agenesis/dysgenesis/hypoplasia, microphthalmia/anophthalmia, and a diaphragmatic defect (agenesis or eventration) is a rare syndrome presumed to have an autosomal recessive mode of inheritance based on a report of affected siblings born to unaffected parents [Seller et al., 1996]. The condition is known as Spear syndrome and Matthew-Wood syndrome, although genetic heterogeneity cannot be ruled out. We report on eight patients with this condition including a living child, three sibs and three isolated cases. Most presented with fetal ultrasound findings of microphthalmia/anophthalmia, and diaphragmatic eventration/hernia and in five, cardiac abnormalities were also found. The earliest detection was at 20 weeks gestation. This is the second report of sibs affected with this condition, which supports an autosomal recessive mode of inheritance. We present the first and only reported living patient with this condition and expand the intrafamilial, interfamilial, and ethnic variability of this condition. We suggest changing the condition's name to PDAC to reflect the most important components of this condition.

Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia–Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).

Diversity of Neuromuscular Pathology in Lethal Multiple Pterygium Syndrome

Lethal multiple pterygium syndrome (LMPS) is an uncommon fetal-onset disorder of unknown etiology. The pathogenesis of LMPS has been suggested to be early-onset fetal akinesia, fragile collagen, or generalized edema. Information on the neuromuscular pathology of LMPS in the literature is generally scanty. We present the findings from a review of 14 fetuses with features of LMPS from the archives of the Hammersmith Hospital Perinatal Pathology Department. Autopsy reports, photographs, fetograms, and histological sections were examined, and additional special stains and immunostaining were performed on muscle sections. In five cases, there was evidence of autosomal recessive inheritance. One case was later shown to be due to glycogen storage disease type IV. The skeletal muscle bulk was reduced in all fetuses and the remaining muscle showed a range of histological appearances including vacuolar degeneration, dystrophy, a generalized or patchy myotubular appearance, and generalized hypotrophy. In one, the histological appearance was essentially normal. Two cases had abnormalities in the brain. Large motor neurons were present in the anterior spinal horns of all fetuses in whom the spinal cord could be examined. There was no evidence of cartilaginous joint fusion. We conclude that LMPS is the phenotype resulting from fetal akinesia commencing in the first or early second trimester. In the majority of cases, the precise underlying cause will not be identified, however, occasionally a metabolic or neurodevelopmental disorder or a specific primary myopathy may be demonstrated, providing adequate autopsy investigations are undertaken.

Two siblings with early onset fetal akinesia deformation sequence and hydranencephaly: Further evidence for autosomal recessive inheritance of hydranencephaly, fowler type

We report a 13-week-old female fetus with early onset fetal akinesia deformation sequence (FADS) and hydranencephaly. In a previous pregnancy, the same ultrasonographic findings were noted at 13 weeks. Fetopathological examination of both female fetuses confirmed FADS with severe arthogryposis, multiple pterygia, and muscular hypoplasia. Neuropathological examination showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brain stem and a proliferative vasculopathy throughout the central nervous system. The findings in the two female siblings document the earliest echographic diagnosis of hydranencephaly, Fowler type, and this observation further supports autosomal recessive inheritance of this distinct type of hydranencephaly. © 2002 Wiley-Liss, Inc.

Two siblings with early onset fetal akinesia deformation sequence and hydranencephaly: Further evidence for autosomal recessive inheritance of hydranencephaly, fowler type

We report a 13-week-old female fetus with early onset fetal akinesia deformation sequence (FADS) and hydranencephaly. In a previous pregnancy, the same ultrasonographic findings were noted at 13 weeks. Fetopathological examination of both female fetuses confirmed FADS with severe arthogryposis, multiple pterygia, and muscular hypoplasia. Neuropathological examination showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brain stem and a proliferative vasculopathy throughout the central nervous system. The findings in the two female siblings document the earliest echographic diagnosis of hydranencephaly, Fowler type, and this observation further supports autosomal recessive inheritance of this distinct type of hydranencephaly.

Bilateral tibial agenesis with ectrodactyly (OMIM 119100): Further evidence for autosomal recessive inheritance

We present further evidence for autosomal recessive inheritance of the bilateral tibial agenesis/ectrodactyly dysostosis. A consanguineous Turkish couple gave birth to three children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia and also had tibial agenesis and ectrodactyly. A second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of three unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of tibiae and symmetrical ectrodactyly of hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirms the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia. © 2001 Wiley-Liss, Inc.

Bilateral tibial agenesis with ectrodactyly (OMIM 119100): Further evidence for autosomal recessive inheritance

We present further evidence for autosomal recessive inheritance of the bilateral tibial agenesis/ectrodactyly dysostosis. A consanguineous Turkish couple gave birth to three children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia and also had tibial agenesis and ectrodactyly. A second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of three unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of tibiae and symmetrical ectrodactyly of hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirms the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia.

Evidence for autosomal recessive inheritance of infantile dilated cardiomyopathy: studies from the Eastern Province of Saudi Arabia.

Familial dilated cardiomyopathy is being increasingly recognized, but affected individuals <10 y are rarely identified. We describe the natural history of dilated cardiomyopathy and evaluate the mode of inheritance among infants of Arab descent from the Eastern Province of Saudi Arabia. We evaluated 55 consecutive cases of dilated cardiomyopathy in patients <10 y of age seen during a 5-y interval. Echocardiography was the primary diagnostic modality. The 55 cases represented 20% of the offspring of 41 families of Arab descent. In 19 families (46%), parents were first cousins; there was no obvious consanguinity in 22 families (54%). Age at presentation was <30 mo (95%) (range, 1 to 100 mo); males (38%) and females (62%) were affected. Patients died (25 patients, 46%), improved (15 patients, 27%), or recovered (15 patients, 27%). The left ventricular shortening fraction at diagnosis ranged from 5 to 28% and did not differ in those who died, improved, or recovered. Complex segregation analysis of the family data using the mixed model of inheritance showed that a model of recessive inheritance best fits the data. Recessively inherited dilated cardiomyopathy has been infrequently reported, perhaps because it may be difficult to recognize in other patient groups in which consanguineous marriage is uncommon and the number of children per family is small. In the setting of consanguineous marriage, homozygosity mapping should lead to identification of the gene(s) causing dilated cardiomyopathy in the families we studied.

Palmoplantar hyperkeratosis in Irish terriers: evidence of autosomal recessive inheritance.

An abnormal development of the epidermis of the footpad was observed in Irish terriers. At the age of six months, the affected animals developed smooth parchment-like footpads. The pad epidermis then hardened and grew lateral cone-like protrusions of up to 5 mm in diameter. Fissures and cracks developed and these predisposed the animal to secondary infection. The repeated occurrence in subsequent generations led to the assumption of a hereditary form of hyperkeratosis. Evidence for an autosomal recessive mode of inheritance was derived from a retrospective analysis of the breeder's records. The clinical, histopathological and ultrastructural features of the disease are presented and the genetic transmission and its implications discussed.