Eur J Med Genet [JOURNAL]
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200 papers
Evaluating ClinGen variant curation expert panels' application of PVS1 code.
Wang X, Li H, Luo H … +4 more , Zou Y, Li H, Qin Y, Song J
Eur J Med Genet · 2024 Feb · PMID 38199457 · Publisher ↗
BACKGROUND: The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines articulates that the effects of certain types of variants on gene function can often...
BACKGROUND: The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines articulates that the effects of certain types of variants on gene function can often be seen as a complete absence of the gene product by leading to a lack of transcription or nonsense-mediated decay(NMD). However, detailed information considering different types of loss of function(LOF) variants, refined steps assimilating details concerning location of variant, changes in strength levels, NMD boundary, or any additional information pointing to a true null effect, were all left to expert judgement. As part of its Clinical Genome Resource (ClinGen) initiative, Variant Curation Expert Panels (VCEPs) are designated to make gene/disease-centric specifications in accordance with the ACMG/AMP guidelines, including a more detailed definition of what constitutes an appropriate LOF evidence. Our goal was to evaluate the current LOF guidelines developed by the VCEPs and analyse the prior curated variants concerning the PVS1 criteria, bringing people occupied in genetic data analysis a comprehensive understanding of this code. METHODS: Our study evaluated 7 VCEPs for their LOF criteria (PVS1). Subsequently, we assessed the predictive criteria by considering the underlying disease mechanism, protein transcript, and variant types delineated. Then, we meticulously curated the LOF evidence referenced by each VCEP in their preliminary variant classification, thereby scrutinizing the recommendations put forth by VCEPs and their application in the interpretation of the aforementioned predictive criteria. Based on these, an extensive curation of evidence summary considering PVS1 applied by VCEPs according to their classification of pilot variants for the purpose of analyzing VCEP criteria specifications and their use in the understanding of LOF was conducted. RESULTS: We observed in this article that the VCEPs discussed followed the majority of Sequence Variant Interpretation (SVI) recommendations concerning the application of this LOF criteria, except for some disease/gene specific considerations. We highlighted the wide range of PVS1 strength levels approved by VCEP, reflecting the diversity of evidence for each variants type. In addition, we observed substantial differences in the approach used to determine relative strengths for different types of null variants and in the attitude towards these principles concerning variant location, NMD and influence to protein function between VCEPs. CONCLUSIONS: It is difficult to understand the intricacies of the predictive data(PVS1), which often requires expert-level knowledge of disease/gene. The VCEP criteria specifications for the predictive evidence play an important role in making it more accessible for the curators to apply the predictive data by providing details concerning this complex criteria. Despite this, we believe there is a need for more guidance on standardizing this process and ensuring consistency in the application of this predictive evidence.
Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression.
Juul-Dam KL, Shukla NN, Cooper TM … +6 more , Cuglievan B, Heidenreich O, Kolb EA, Rasouli M, Hasle H, Zwaan CM
Eur J Med Genet · 2023 Dec · PMID 38174649 · Full text
Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and...
Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulation of HOXA and HOXB homeobox genes and myeloid ecotropic virus insertion site 1 (MEIS1). Aberrant HOXA/MEIS1 expression is associated with genotypes such as rearrangements in Histone-lysine N-methyltransferase 2A (KMT2A-r), nucleoporin 98 (NUP98-r) and mutated nucleophosmin (NPM1c) that are found in approximately one third of children with AML. AML with upregulated HOXA/MEIS1 shares a number of molecular vulnerabilities amenable to recently developed molecules targeting the assembly of protein complexes or transcriptional regulators. The interaction between the nuclear scaffold protein menin and KMT2A has gained particular interest and constitutes a molecular dependency for maintenance of the HOXA/MEIS1 transcription program. Menin inhibitors disrupt the menin-KMT2A complex in preclinical models of KMT2A-r, NUP98-r and NPM1c acute leukemias and its occupancy at target genes leading to leukemic cell differentiation and apoptosis. Early-phase clinical trials are either ongoing or in development and preliminary data suggests tolerable toxicities and encouraging efficacy of menin inhibitors in adults with relapsed or refractory KMT2A-r and NPM1c AML. The Pediatric Acute Leukemia/European Pediatric Acute Leukemia (PedAL/EUPAL) project is focused to advance and coordinate informative clinical trials with new agents and constitute an ideal framework for testing of menin inhibitors in pediatric study populations. Menin inhibitors in combination with standard chemotherapy or other targeting agents may enhance anti-leukemic effects and constitute rational treatment strategies for select genotypes of childhood AML, and provide enhanced safety to avoid differentiation syndrome. In this review, we discuss the pathophysiological mechanisms in KMT2A-r, NUP98-r and NPM1c AML, emerging molecules targeting the HOXA/MEIS1 transcription program with menin inhibitors as the most prominent examples and future therapeutic implications of these agents in childhood AML.
Fetal hepatic calcification in severe KAT6A (Arboleda-Tham) syndrome.
Di Caprio A, Rossi C, Bertucci E … +8 more , Bedetti L, Bertoncelli N, Miselli F, Corso L, Bondi C, Iughetti L, Berardi A, Lugli L
Eur J Med Genet · 2024 Feb · PMID 38143025 · Publisher ↗
Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of...
Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of KAT6A syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach. In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift KAT6A pathogenic variant, displaying a severe phenotype with previously unreported clinical features.
Genetic counselling supervision: Luxury or necessity? A qualitative study with genetic healthcare professionals in Portugal.
Guimarães L, Baião R, Costa C … +3 more , Lemos M, Henriques MR, Paneque M
Eur J Med Genet · 2024 Feb · PMID 38143024 · Publisher ↗
In recent years, there has been a significant technological evolution in the field of genetics, leading to an increase in the number of professionals working in medical genetics and, consequently, a tremendous growth in...
In recent years, there has been a significant technological evolution in the field of genetics, leading to an increase in the number of professionals working in medical genetics and, consequently, a tremendous growth in genetic counselling. At the same time, there has been a growing recognition of the parameters on which to base a safe practice, not only regarding the technical skills of the professional but also regarding their counselling skills, including relational and empathy skills and the acknowledgement of the emotional impact that genetic counselling practice can have. However, despite this growing knowledge, there are still significant differences between the various European countries, and one area where this discrepancy is particularly evident is genetic counselling supervision. Thus, if there are countries where genetic counselling supervision is not even known by the professionals, there are others where it is mandatory for practice. This research had as an objective to understand if and how genetic counselling supervision is provided in Portugal, to identify routines, challenges and impacts of genetic counselling that should be explored in a supervision process and comprehend how professionals believe supervision should be conducted to be effective. A total of sixteen medical geneticists from main Portuguese genetic services were present in two online focus groups. None of the participants had access to genetic counselling supervision as a programmed routine and there was a consensus that a service of this kind would be particularly important for the professionals as genetic counselling has frequently challenging and emotional moments. Aspects regarding clinical supervision, the characteristics of the supervisor and the practical aspects of genetic counselling supervision implementation were also mentioned during the discussions. These results highlight the relevancy of the establishment of GC supervision routines and standardized guidelines in our country, as well as a need for evidence-based research focused on its impact at professional and practice level.
The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.
Devoogdt N, Thomis S, Belva F … +17 more , Dickinson-Blok J, Fourgeaud C, Giacalone G, Karlsmark T, Kavola H, Keeley V, Marques ML, Mansour S, Nissen CV, Nørregaard S, Oberlin M, Ručigaj TP, Somalo-Barranco G, Suominen S, Van Duinen K, Vignes S, Damstra R
Eur J Med Genet · 2024 Feb · PMID 38143023 · Publisher ↗
Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production...
Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.
Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: clinical report and review of the literature.
Moroni A, Brizola E, Di Cecco A … +6 more , Tremosini M, Sergiampietri M, Bianchi A, Tappino B, Piana M, Gnoli M
Eur J Med Genet · 2024 Feb · PMID 38141876 · Publisher ↗
Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent no...
Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in CTSK gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing. We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of CTSK gene revealed the presence of the pathogenic homozygous variant c.746T>A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis. We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature. This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.
Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype.
Harkness JR, Thomas HB, Urquhart JE … +6 more , Jamieson P, Genomics England Research Consortium, O'Keefe RT, Kingston HM, Deshpande C, Newman WG
Eur J Med Genet · 2024 Feb · PMID 38141875 · Full text
Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 ye...
Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.
Associated anomalies in anophthalmia and microphthalmia.
Stoll C, Dott B, Alembik Y … +1 more , Roth MP
Eur J Med Genet · 2024 Feb · PMID 38110175 · Publisher ↗
Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The pu...
Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The purpose of this investigation was to assess the frequency and the types of associated anomalies among cases with an/microphthalmia in a geographically well defined population of northeastern France of 387,067 consecutive pregnancies from 1979 to 2007. Of the 98 infants with an/microphthalmia born during this period (prevalence at birth of 2.53 per 10,000), 88.8 % had associated anomalies. Cases with associated anomalies were divided into recognizable conditions (25 (25.5%) cases with chromosomal and 17 (17.3%) cases with non chromosomal conditions), and non recognizable conditions (45-45.9%- cases with multiple congenital anomalies -MCA). Trisomy 13 and trisomy 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, oculo-auriculo-vertebral spectrum, CHARGE syndrome and VACTERL association were most often present in recognizable non chromosomal conditions. Anomalies in the musculoskeletal, cardiovascular and central nervous systems were the most common other anomalies in cases with MCA and non recognizable conditions. However, given the limitation of the limited numbers of cases there should be urging caution in interpreting these results. In conclusion the frequency of associated anomalies in infants with anophthalmia and microphthalmia emphasizes the need for a thorough investigation of these cases. Routine screening for other anomalies especially musculoskeletal, cardiac and central nervous systems anomalies may need to be considered in infants with anophthalmia and microphthalmia, and referral of these cases for genetic counselling seems warranty.
LRP4 site-specific variants in the third β-propeller domain causes congenital myasthenic syndrome type 17.
Al Jabry T, Al-Hashmi N, Abdelhadi B … +1 more , Al-Maawali A
Eur J Med Genet · 2024 Feb · PMID 38101565 · Publisher ↗
LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction...
LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third β-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).
Combined achondroplasia and short stature homeobox-containing (SHOX) gene deletion in a Danish infant.
Seiersen KV, Henriksen TB, Andelius TCK … +6 more , Andreasen L, Diemer T, Gudmundsdottir G, Vogel I, Gjørup V, Gregersen PA
Eur J Med Genet · 2024 Feb · PMID 38070826 · Publisher ↗
Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblas...
Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3). Short stature homeobox (SHOX) deficiency is caused by loss or defects of the SHOX gene or its enhancer region. It is associated with a spectrum of phenotypes ranging from normal stature to Léri-Weill dyschondrosteosis characterized by mesomelia and short stature or the more severe Langer mesomelic dysplasia in case of biallelic SHOX deficiency. Little is known about the interactions and phenotypic consequences of achondroplasia in combination with SHOX deficiency, as the literature on this subject is scarce, and no genetically confirmed clinical reports exist. We present the clinical findings in an infant girl with concurrent achondroplasia and SHOX deficiency. We conclude that the clinical findings in infancy are phenotypically compatible with achondroplasia, with no features of the SHOX deficiency evident. This may change over time, as some features of SHOX deficiency only become evident later in life.
GRM7-related disorder: five additional patients from three independent families and review of the literature.
Januel L, Chatron N, Rivier-Ringenbach C … +9 more , Cabet S, Labalme A, Sahin Y, Darvish H, Kruer M, Bakhtiari S, Sanlaville D, de Sainte Agathe JM, Lesca G
Eur J Med Genet · 2024 Feb · PMID 38070825 · Publisher ↗
Developmental and epileptic encephalopathies (DEEs) refer to a group of severe epileptic syndromes characterized by seizures as well as a developmental delay which can be a consequence of the underlying etiology and/or t...
Developmental and epileptic encephalopathies (DEEs) refer to a group of severe epileptic syndromes characterized by seizures as well as a developmental delay which can be a consequence of the underlying etiology and/or the epileptic encephalopathy. The genes responsible for DEEs are numerous and their number is increasing since the availability of Next-Generation Sequencing. Pathogenic variants in GRM7, encoding the metabotropic glutamate receptor 7, were recently shown as a cause of a severe DEE with autosomal recessive inheritance. To date, only ten patients have been reported in the literature, generally with severe phenotypes including early-onset epilepsy, microcephaly, brain anomalies, and spasticity. We report here 5 patients from 3 independent families with biallelic variants in the GRM7 gene. We review the literature and provide further elements for the understanding of the genotype-phenotype correlation of this rare syndrome.
Progressive myoclonic epilepsy as an expanding phenotype of NGLY1-associated congenital deglycosylation disorder: A case report and review of the literature.
Sonoda Y, Fujita A, Torio M … +18 more , Mukaino T, Sakata A, Matsukura M, Yonemoto K, Hatae K, Ichimiya Y, Chong PF, Ochiai M, Wada Y, Kadoya M, Okamoto N, Murakami Y, Suzuki T, Isobe N, Shigeto H, Matsumoto N, Sakai Y, Ohga S
Eur J Med Genet · 2024 Feb · PMID 38070824 · Publisher ↗
INTRODUCTION: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoprotein...
INTRODUCTION: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive. CASE PRESENTATION: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1. CONCLUSION: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.
Secondary physical features in children with FASD.
Del Campo M, Kable JA, Coles CD … +3 more , Suttie M, Chambers CD, Bandoli G
Eur J Med Genet · 2024 Feb · PMID 38042254 · Full text
OBJECTIVE: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical...
OBJECTIVE: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical features and neurobehavioral impairments. Although 3 key facial features (short palpebral fissures, a smooth philtrum and a thin vermilion of the upper lip) are the only dysmorphic features taken into account for the diagnosis of Fetal Alcohol Syndrome (FAS) or partial FAS (pFAS), several other features are commonly seen in individuals with these diagnoses. The goals of our study were to determine if some of these secondary physical features also occur more frequently in children with alcohol-related neurodevelopmental disorder (ARND) relative to controls, and if a cluster of these features combined in a dysmorphology score could be used to identify those negatively impacted by PAE but who do not have the cardinal physical features that led to a diagnosis of FAS or pFAS. METHODS: Among 2681 children recruited for the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP) study, 1726 had an FASD or sufficient evidence of PAE having occurred or not in their pregnancy. Children were then categorized into groups using the modified Hoyme diagnostic criteria (FAS (n = 24), pFAS (n = 99) and ARND (n = 87), and No FASD (n = 1516), including those with No FASD and a history of PAE (No FASD/PAE, n = 498) and those with No FASD and no history of PAE (No FASD/No PAE, n = 1018). The frequencies of 26 secondary dysmorphic features were compared among these groups, both individually and combined in non-weighted and weighted dysmorphic scores. Correlations of the total dysmorphic scores with an index of overall cognitive ability were also compared by group status. RESULTS: Several of these features were significantly more frequent in children with FAS than in those with No FASD diagnosis with or without PAE but not in comparison to those with ARND. The number of features was also significantly higher in the FAS group as compared to all other groups for both weighted and unweighted dysmorphology scores but were not higher in the group with ARND when compared to the groups with No FASD either in the presence or absence of PAE. Although not diagnostic, higher total dysmorphology scores were predictive of lower general cognitive abilities in the group with ARND, suggesting severity of alcohol-related dysmorphology is predictive of severity of alcohol-related neurobehavioral impairment. CONCLUSION: Secondary physical features were not more frequent in children with ARND compared to children without an FASD diagnosis but were a marker for lower cognitive function. The use of secondary physical features to support a diagnosis of ARND was not supported in this sample.
Defining priorities in the transition from paediatric to adult healthcare for rare bone disease patients: a dialogic approach.
Scognamiglio D, Boarini M, la Forgia MC … +6 more , Grippa E, Forni S, Sergi A, Romeo A, Massa G, Sangiorgi L
Eur J Med Genet · 2024 Feb · PMID 38040052 · Publisher ↗
The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual conference. The study inc...
The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual conference. The study included the Open Dialogue Approach and a feedback survey to identify the main priorities in the transitioning process from paediatric to adult healthcare for patients with Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome. The common needs identified by patients, families, caregivers, and healthcare professionals were coordination and continuity of care, patient empowerment and communication, social and practical support, and transition planning and support. This experience fostered a sense of collaboration and cooperation among stakeholders, helping to build trust and create a shared vision for improving the quality of care for these patients. Furthermore, it could be considered a starting point for other patient associations interested in using different approaches to identify the needs of their members and actively involve all stakeholders.
New description of an MRPS2 homozygous patient: Further features to help expend the phenotype.
Papadopoulos T, Gaignard P, Schiff M … +5 more , Rio M, Karall D, Legendre A, Verloes A, Ruaud L
Eur J Med Genet · 2024 Feb · PMID 38029925 · Publisher ↗
Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects, two with sensorineural hearing impairment, mild developmental delay, hypoglycemia, lactic acidemia and combined oxidative phosphoryl...
Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects, two with sensorineural hearing impairment, mild developmental delay, hypoglycemia, lactic acidemia and combined oxidative phosphorylation system deficiency and another, recently, presenting with a less severe phenotype. In order to expand the phenotype, we describe a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features.
Early-onset diabetes in Africa: A mini-review of the current genetic profile.
Adadey SM, Mensah JA, Acquah KS … +2 more , Abugri J, Osei-Yeboah R
Eur J Med Genet · 2023 Dec · PMID 37995864 · Publisher ↗
Early-onset diabetes is poorly diagnosed partly due to its heterogeneity and variable presentations. Although several genes have been associated with the disease, these genes are not well studied in Africa. We sought to...
Early-onset diabetes is poorly diagnosed partly due to its heterogeneity and variable presentations. Although several genes have been associated with the disease, these genes are not well studied in Africa. We sought to identify the major neonatal, early childhood, juvenile, or early-onset diabetes genes in Africa; and evaluate the available molecular methods used for investigating these gene variants. A literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. The retrieved records were screened and analyzed to identify genetic variants associated with early-onset diabetes. Although 319 records were retrieved, 32 were considered for the current review. Most of these records (22/32) were from North Africa. The disease condition was genetically heterogenous with most cases possessing unique gene variants. We identified 22 genes associated with early-onset diabetes, 9 of which had variants (n = 19) classified as pathogenic or likely pathogenic (PLP). Among the PLP variants, IER3IP1: p.(Leu78Pro) was the variant with the highest number of cases. There was limited data from West Africa, hence the contribution of genetic variability to early-onset diabetes in Africa could not be comprehensively evaluated. It is worth mentioning that most studies were focused on natural products as antidiabetics and only a few studies reported on the genetics of the disease. ABCC8 and KCNJ11 were implicated as major contributors to early-onset diabetes gene networks. Gene ontology analysis of the network associated ion channels, impaired glucose tolerance, and decreased insulin secretions to the disease. Our review highlights 9 genes from which PLP variants have been identified and can be considered for the development of an African diagnostic panel. There is a gap in early-onset diabetes genetic research from sub-Saharan Africa which is much needed to develop a comprehensive, efficient, and cost-effective genetic panel that will be useful in clinical practice on the continent and among the African diasporas.
Resolving fetal hydrops - A rare entity.
Saxena D, Tiwari AK, Prasad R … +1 more , Srivastav S
Eur J Med Genet · 2023 Dec · PMID 37993095 · Publisher ↗
Non-immune hydrops fetalis (NIHF) is abnormal accumulation of serous fluid in ≥2 interstitial spaces with no evidence of maternal red cell alloimmunization. Leaving a few treatable conditions, it is generally considered...
Non-immune hydrops fetalis (NIHF) is abnormal accumulation of serous fluid in ≥2 interstitial spaces with no evidence of maternal red cell alloimmunization. Leaving a few treatable conditions, it is generally considered as a sign of poor fetal outcome. Bi-allelic variants in THSD1 have been found to be to be associated with phenotypes ranging from lethal NIHF to persistent edema. Here, we report a family with non-immune hydrops in two successive pregnancies. Whole exome sequencing in second pregnancy identified a homozygous truncating variant in THSD1 (NM_018676:c.892G>T:p.Glu298Ter). Postnatal follow up showed gradual resolution of the accumulated fluid and normal development. This report further strengthens the association of variants in THSD1 with NIHF.
Clinical and molecular features of four families with CLDN10-related HELIX syndrome.
Qudair A, Hussein M, Alowain M … +5 more , Al-Hassnan ZN, Alfaifi A, Alfalah A, Al-Qahtani M, Alkuraya FS
Eur J Med Genet · 2023 Dec · PMID 37984702 · Publisher ↗
Biallelic pathogenic variants in CLDN10 cause the very rare and distinct multiplex epithelium dysfunction manifested by hypohidrosis and electrolyte imbalance (HELIX) syndrome. HELIX patients often present with heat into...
Biallelic pathogenic variants in CLDN10 cause the very rare and distinct multiplex epithelium dysfunction manifested by hypohidrosis and electrolyte imbalance (HELIX) syndrome. HELIX patients often present with heat intolerance and reduced tear secretion. Here, we report on eight new patients (four families) who presented soon after birth with fine scales in the palms and soles and hypohidrosis that was associated with high body temperature. Exome sequencing identified a novel homozygous pathogenic variant in CLDN10 in one family (NM_006984:exon1:c.138G>A:p.W46*) and a previously reported pathogenic founder variant in the other three (NM_006984:exon5:c.653del:P218Lfs*21). The detailed clinical reports of these patients and a review of previously reported patients further delineate the phenotype of this extremely rare disorder.
Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review.
Monda E, Bakalakos A, Syrris P … +4 more , Mohiddin S, Ferdinandusse S, Murphy E, Elliott PM
Eur J Med Genet · 2023 Dec · PMID 37979716 · Publisher ↗
BACKGROUND: Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe t...
BACKGROUND: Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. METHODS: Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. RESULTS: Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). CONCLUSIONS: For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.
Response to the comment on Diderich et al. "The role of a multidisciplinary team in managing variants of uncertain clinical significance in prenatal genetic diagnosis" (EJMG 66(10),104844).
Diderich KEM, Klapwijk JE, van der Schoot V … +8 more , van den Born M, Wilke M, Joosten M, Stuurman KE, Hoefsloot LH, Van Opstal D, Brüggenwirth HT, Srebniak MI
Eur J Med Genet · 2024 Feb · PMID 37972850 · Publisher ↗
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