Yin X, Lin Y, Zhang T
… +6 more, Miao H, Hu L, Hu Z, Zhou D, Wu B, Huang X
Eur J Med Genet
· 2024 Jun · PMID 38830573
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Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot detect non-classic CAH and has high false positive rat...Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot detect non-classic CAH and has high false positive rates. We have developed a novel MALDI-TOF MS assay that can identify common variants and deletions of CYP21A2 in the Chinese population. Thirty-seven clinical patients with CAH confirmed by Sanger sequencing and MLPA analysis were detected by MALDI-TOF MS assay. Two CYP21A2 variants were detected in 30 patients and one CYP21A2 variant was detected in 7 patients. The MALDI-TOF MS assay detected 67 mutant alleles in 37 patients with a detection rate of 90.5%. Sanger sequencing revealed that three variants in seven patients were not included in the designed panel. Eleven distinct CYP21A2 variants were identified, including five missense variants, two nonsense variants, two large gene deletions, one splice variant, and one frameshift variant. The most frequent variant was c.293-13C > G (37.84%), followed by c.518T > A (21.62%) and exon 1-7 deletion (17.57%). The high-throughput MALDI-TOF MS assay that can simultaneously detect common variants and deletions of CYP21A2. This assay can be used for population-based genetic screening and rapid detection of suspected patients, and is expected to be a valuable complement to biochemical-based testing for the detection of CAH.
van der Smagt JJ, Lampri AP, de Lange I
… +4 more, Alders M, Houben ML, Koudijs MJ, van Jaarsveld RH
Eur J Med Genet
· 2024 Jun · PMID 38797245
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Variation in the non-coding genome is being increasingly recognized to be involved in monogenic disease etiology. However, the interpretation of non-coding variation is complicated by a lack of understanding of how non-c...Variation in the non-coding genome is being increasingly recognized to be involved in monogenic disease etiology. However, the interpretation of non-coding variation is complicated by a lack of understanding of how non-coding genetic elements function. Additional lines of evidence are therefore needed to recognize non-coding variants as pathogenic. We here present a case where a collective body of evidence resulted in the identification and conclusive classification of a pathogenic deep intronic variant in ATRX. This report demonstrates the utility of a multi-platform approach in aiding the identification of pathogenic variants outside coding regions. Furthermore, it marks the first reported instance of a deep intronic pathogenic variant in ATRX.
Alharbi R, Suchet-Dechaud A, Harzallah I
… +2 more, Touraine R, Ramond F
Eur J Med Genet
· 2024 Jun · PMID 38735569
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Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly understood. We repor...Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly understood. We report a 4-year-old girl who initially presented with an isolated ARM, and subsequently developed a global developmental delay as part of an ARID1B-related Coffin-Siris syndrome (CSS). A co-occurrence of ARMs and CSS in an individual by chance is unexpected since both diseases are very rare. A review of the literature enabled us to identify 10 other individuals with both CSS and ARMs. Among the ten individuals reported in this study, 8 had a variant in ARID1A, 2 in ARID1B, and 1 in SMARCA4. This more frequent than expected association between CSS and ARM indicates that some ARMs are most likely part of the CSS spectrum, especially for ARID1A-related CSS.
Abughofah Y, Witten AJ, Belal A
… +1 more, Wilson S
Eur J Med Genet
· 2024 Jun · PMID 38729602
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BACKGROUND: Nablus mask-like facial syndrome (NMFLS) is an extremely rare genetic syndrome characterized by facial dysmorphia as well as developmental delay. In the present report we describe a potential association betw...BACKGROUND: Nablus mask-like facial syndrome (NMFLS) is an extremely rare genetic syndrome characterized by facial dysmorphia as well as developmental delay. In the present report we describe a potential association between non-traumatic atlanto-occipital dislocation and NMFLS in an 11-year old female lacking typical facial features of NMFLS. CASE DESCRIPTION: An 11-year-old female with autism presented with symptoms of persistent headache and vomiting as well as neck stiffness. Further investigation and CT imaging revealed congenital malformation of the skull base and craniocervical junction with complete posterior subluxation of the left occipital condyle. MRI findings later corroborated the findings on CT. CONCLUSIONS: The patient was successfully treated with occipitocervical fusion. The findings in this case suggest the possibility that atlanto-occipital instability and generalized occipitocervical may be associated with NMFLS.
Eur J Med Genet
· 2024 Jun · PMID 38705458
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Larsen of La Réunion Island syndrome (LRS) is an autosomal recessive condition associated with multiple large joint dislocations, clubfeet, severe dwarfism, and distinctive facial features. LRS is caused by a recurrent h...Larsen of La Réunion Island syndrome (LRS) is an autosomal recessive condition associated with multiple large joint dislocations, clubfeet, severe dwarfism, and distinctive facial features. LRS is caused by a recurrent homozygous variant in B4GALT7 gene with a founder effect in La Réunion population. Proteoglycans (PG) that are a major component of the extracellular matrix, are composed of a core protein connected to a glycosaminoglycans side chain via a tetrasaccharide linker region. B4GALT7 encodes galactosyltransferase I, one of the enzymes involved in the biosynthesis of the linker region. Conditions caused by pathogenic biallelic variants in genes implicated in the synthesis of the tetrasaccharide linker of PG are known as linkeropathies. Prenatal features are rarely described in this group of chondrodysplasias. We present a series of 12 unpublished patients having LRS and describe the perinatal phenotype. All the patients had a prenatal growth restriction with brevity of limbs. The other features revealed by ultrasounds were increased nuchal translucency at 10-12 weeks of gestation (50 %), feet abnormalities (clubfeet or metatarsus varus) (25 %), dislocation affecting at least one large joint (elbow, knee, wrist) (25 %). Bilateral bowing of femora was noted for two fetuses. Fibular hypertrophy was noted for one fetus. Prenatal helical computed tomography (CT) performed in three pregnancies showed additional data such as bowing of the forearm bones, proximal radio-ulnar synostosis, or dislocation of large joints. Prenatal sonographic and helical CT findings led to the prenatal diagnosis of LRS in four patients. We confirm that the neonatal clinical picture of LRS has an important overlap with that reported in patients with B4GALT7 deficiency outside La Réunion Island and other linkeropathies. The core of the phenotypic spectrum combines low birth height, micromelia, hypermobility, dislocation of at least one large joint, facial features with prominent eyes, microstomia, depressed nasal bridge, and midface hypoplasia. Other clinical features include clubfeet (33%), bifid thumb in one patient, and cardiac abnormalities in two patients. Radiological findings include radio-ulnar synostosis (75%), metaphyseal flaring, precocious carpal ossification, and a Swedish key appearance of the proximal femora. Finally, we also report radiological features rarely described in B4GALT7-linkeropathies, including bowing of the femora and fibular hypertrophy. Our results confirm the phenotypic continuum of LRS within linkeropathies with some additional findings, including a high frequency of clubfeet usually described in B3GALT6-linkeropathies, the presence of congenital heart diseases usually described in B3GAT3-linkeropathies, and a high frequency of metaphyseal flaring usually reported in B3GALT6 or XITLT1-linkeropathies. This is the first study that describes the perinatal phenotype in a cohort of patients with LRS. This study can help improve the prenatal diagnosis of the linkeropathies and add this group of conditions to the differential diagnosis of chondrodysplasias with multiple dislocations. In view of the founder effect for LRS in La Réunion Island, this disease should be suspected in fetuses with growth restriction and micromelia. Thus in case of LOH which include B4GALT7 identified in SNP-array, we recommend performing a targeted Sanger sequencing for the recurrent mutation c.808C > T; p. (Arg270Cys).
Eur J Med Genet
· 2024 Jun · PMID 38705457
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Germline MICAL1 defects have been rarely reported in patients with epilepsy and the genotype-phenotype association remains unclear. In this study, the patient was a 4.6 years old girl who presented with onset of recurren...Germline MICAL1 defects have been rarely reported in patients with epilepsy and the genotype-phenotype association remains unclear. In this study, the patient was a 4.6 years old girl who presented with onset of recurrent focal seizures with onset at age 3.4 years. EEG showed abnormal δ-wave activity in the right central and middle temporal lobe. Trio WES showed a novel heterozygous variant c.-43-1G > A in the MICAL1 gene in the patient and her normal mother. Minigene verified two abnormal transcripts due to the mutation, which was predicted to interrupt 5'UTR structures of MICAL1. The patient was clinically diagnosed with benign childhood epilepsy with centrotemporal spike (BECTS). As far as we know, this is the first BECTS case with documented MICAL1 mutation. Novel MICAL1 variant c.-43-1G > A putatively interrupted MICAL1 translation by changing 5'UTR structures and, however, further functioning study is needed.
Kolokotronis K, Suter AA, Ivanovski I
… +4 more, Frey T, Bahr A, Rauch A, Steindl K
Eur J Med Genet
· 2024 Jun · PMID 38697389
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To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which loca...To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2. Here we report on the first familial case of Coffin-Siris syndrome type 7. The index patient presented during the 1st year of life with failure to thrive and ectodermal anomalies. The genetic analysis using whole exome sequencing showed a likely pathogenic missense variant in the PHD1 region. The family analysis showed that the mother as well as the older brother of the index patient also carried the detected DPF2 variant in heterozygous state. The mother had a history of school difficulties but no history of failure to thrive and was overall mildly affected. The brother showed developmental delay with autistic features, ectodermal anomalies and overlapping morphologic features but did not have a history of growth failure problems. To our knowledge this is the first report of an inherited likely pathogenic variant in DPF2, underlining the variability of the associated phenotype as well as the importance of considering inherited DPF2 variants during the variant filtering strategy of whole exome data.
Tonelli L, Sanchini M, Margutti A
… +5 more, Buldrini B, Superti-Furga A, Ferlini A, Selvatici R, Bigoni S
Eur J Med Genet
· 2024 Jun · PMID 38679371
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Kenny-Caffey Syndrome (KCS) is a genetic syndrome characterized by growth retardation with short stature, cortical thickening and medullary stenosis of long bones, and hypoparathyroidism with hypocalcemia. KCS and the re...Kenny-Caffey Syndrome (KCS) is a genetic syndrome characterized by growth retardation with short stature, cortical thickening and medullary stenosis of long bones, and hypoparathyroidism with hypocalcemia. KCS and the related but more severe condition osteocraniostenosis are determined by monoallelic variants in the FAM111A gene. Here we describe the KCS phenotype resulting from the monoallelic FAM111A variant p.Y511H in a 31-year-old woman and in her 56-year-old mother, who is one of the oldest affected individuals known so far. To our knowledge, it is also one of the few molecularly confirmed cases of a mother-to-child transmission of KCS.
Mégarbané A, Mehawej C, Mahfoud D
… +6 more, Chouery E, Devriendt K, Hijazi M, Ryu SW, Kim J, McNeill A
Eur J Med Genet
· 2024 Jun · PMID 38679370
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Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those se...Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.2: c.1781A > G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089). Our findings further delineate the clinical spectrum linked to FBXO11 and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation.
Leduc F, Smol T, Catteau B
… +2 more, Boute O, Petit F
Eur J Med Genet
· 2024 Jun · PMID 38677542
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Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at...Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome. We report on the 8th patient carrying a heterozygous de novo variation of PRKD1 c.2134G > A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with PRKD1 missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations. In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.
Mohr A, Marques Da Costa ME, Fromigue O
… +9 more, Audinot B, Balde T, Droit R, Abbou S, Khneisser P, Berlanga P, Perez E, Marchais A, Gaspar N
Eur J Med Genet
· 2024 Jun · PMID 38677541
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High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarco...High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival.
Matsumoto M, Oyake M, Itonaga T
… +7 more, Maeda M, Suenobu S, Sato D, Sasahara Y, Mishima H, Yoshiura KI, Ihara K
Eur J Med Genet
· 2024 Jun · PMID 38614309
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ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and s...ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.
Funck-Brentano T, Zillikens MC, Clunie G
… +3 more, Siggelkow H, Appelman-Dijkstra NM, Cohen-Solal M
Eur J Med Genet
· 2024 Jun · PMID 38593953
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Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of...Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
Eur J Med Genet
· 2024 Aug · PMID 38583555
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Individual researchers and consortia have been studying rare diseases for several decades. However, the rare disease community can be very fragmented mainly due to the large heterogeneity of rare diseases. Indeed, for ma...Individual researchers and consortia have been studying rare diseases for several decades. However, the rare disease community can be very fragmented mainly due to the large heterogeneity of rare diseases. Indeed, for many diseases, there is a very limited amount of researchers and resources available. Concerted efforts to organize the rare disease community and funding were emerging in several countries but so far, international coordination was rather limited. The International Rare Diseases Research Consortium (IRDiRC) aims to correct this. A part of this requires bringing rare disease researchers together for an international conference.
Tėvelytė I, Bertašius P, Aleknavičienė K
… +4 more, Jonikas R, Klimaitė J, Jašinskienė E, Traberg R
Eur J Med Genet
· 2024 Jun · PMID 38580081
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Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is char...Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the NOTCH2 gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of NOTCH2 gene c.6449delC, p.(Pro2150LeufsTer5).
Eur J Med Genet
· 2024 Jun · PMID 38574886
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Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1...Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.
Ciantar N, Zahra G, Delicata J
… +4 more, Sammut F, Calleja-Agius J, Farrugia E, Said E
Eur J Med Genet
· 2024 Jun · PMID 38537868
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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years...BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years of age. The aim of the study was to determine the genetic aetiology in Maltese patients clinically diagnosed with ADPKD and correlate the clinical features. METHODS: A total of 60 patients over 18 years of age clinically diagnosed with ADPKD were studied using a customized panel of genes that had sufficient evidence of disease diagnosis using next generation sequencing (NGS). The genes studied were PKD1, PKD2, GANAB, DNAJB11, PKHD1 and DZIP1L. Selected variants were confirmed by bidirectional Sanger sequencing with specifically designed primers. Cases where no clinically significant variant was identified by the customized gene panel were then studied by Whole Exome Sequencing (WES). Microsatellite analysis was performed to determine the origin of an identified recurrent variant in the PKD2 gene. Clinical features were studied for statistical correlation with genetic results. RESULTS: Genetic diagnosis was reached in 49 (82%) of cases studied. Pathogenic/likely pathogenic variants PKD1 and PKD2 gene were found in 25 and in 23 cases respectively. The relative proportion of genetically diagnosed PKD1:PKD2 cases was 42:38. A pathogenic variant in the GANAB gene was identified in 1 (2%) case. A potentially significant heterozygous likely pathogenic variant was identified in PKHD1 in 1 (2%) case. Potentially significant variants of uncertain significance were seen in 4 (7%) cases of the study cohort. No variants in DNAJB11 and DZIP1L were observed. Whole exome sequencing (WES) added the diagnostic yield by 10% over the gene panel analysis. Overall no clinically significant variant was detected in 6 (10%) cases of the study population by a customized gene panel and WES. One recurrent variant the PKD2 c.709+1G > A was observed in 19 (32%) cases. Microsatellite analysis showed that all variant cases shared the same haplotype indicating that their families may have originated from a common ancestor and confirmed it to be a founder variant in the Maltese population. The rate of decline in eGFR was steeper and progression to ESRD was earlier in cases with PKD1 variants when compared to cases with PKD2 variants. Cases segregating truncating variants in PKD1 showed a significantly earlier onset of ESRD and this was significantly worse in cases with frameshift variants. Overall extrarenal manifestations were commoner in cases segregating truncating variants in PKD1. CONCLUSIONS: This study helps to show that a customized gene panel is the first-line method of choice for studying patients with ADPKD followed by WES which increased the detection of variants present in the PKD1 pseudogene region. A founder variant in the PKD2 gene was identified in our Maltese cohort with ADPKD. Phenotype of patients with ADPKD is significantly related to the genotype confirming the important role of molecular investigations in the diagnosis and prognosis of polycystic kidney disease. Moreover, the findings also highlight the variability in the clinical phenotype and indicate that other factors including epigenetic and environmental maybe be important determinants in Autosomal Dominant Polycystic Kidney Disease.
de Masfrand S, Cogné B, Nizon M
… +19 more, Deb W, Goldenberg A, Lecoquierre F, Nicolas G, Bournez M, Vitobello A, Mau-Them FT, le Guyader G, Bilan F, Bauer P, Zweier C, Piard J, Pasquier L, Bézieau S, Gerard B, Faivre L, Saugier-Veber P, Piton A, Isidor B
Eur J Med Genet
· 2024 Jun · PMID 38453051
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PURPOSE: Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of...PURPOSE: Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance. METHOD: From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study. RESULTS: We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent. CONCLUSION: Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.
OBJECTIVE: This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. MET...OBJECTIVE: This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. METHODS: A retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations. RESULTS: The study comprised five patients (four males, one female) with disease onset at six months of age (range: 0-1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent β-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal β-glucuronidase activity and no disease-causing mutations in the GUSB gene. CONCLUSION: The study's patients all presented with classic symptoms of MPS VII due to β-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.
PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility...PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients. METHODS: Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles' references. Articles were coded to assess definitions and measures of clinical utility. RESULTS: Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members). CONCLUSION: Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.