Neuropsychological profile of French adults with early-treated phenylketonuria: a multicenter study.

Background And Objective: Adult patients with early-treated phenylketonuria (AwET-PKU) may present some subtle neurocognitive deficits. The aim of the study was to investigate 1) neurocognitive functions in a large group of AwET-PKU 2) the influence of plasma phenylalanine (Phe).

Methods: Participants: 187 AwET-PKU (classic PKU [cPKU] 81%, mild PKU [mPKU] 14%, and mild persistent hyperphenylalaninemia [MPH] 5%).

De Novo Balanced Translocations Disrupting the FBN1 Gene Diagnosed by Genome Sequencing: An Uncommon Cause of Marfan Syndrome Modifying Genetic Counseling.

Marfan syndrome (MFS) is a well-characterized rare genetic connective tissue disorder. The features of MFS are primarily skeletal, ocular, and cardiovascular and are mainly caused by single-nucleotide variants (SNVs) in the FBN1 gene (MIM#134797) located on chromosome 15q21.1.

GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment.

Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains.

The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture.

Cilia are essential organelles and variants in genes governing ciliary function result in ciliopathic diseases. The Ciliogenesis and PLANar polarity Effectors (CPLANE) protein complex is essential for ciliogenesis in animals models but remains poorly defined. Notably, all but one subunit of the CPLANE complex have been implicated in human ciliopathy.

[The contribution of cerebral organoids to the understanding and treatment of rare genetic diseases with neurodevelopmental disorders].

Rare genetic diseases with neurodevelopmental disorders (NDDs) encompass several heterogeneous conditions (autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), specific learning disorder (SLD), among others). Currently, few treatments are available for these patients. The difficulty in accessing human brain samples and the discrepancies between human and animal models highlight the need for new research approaches.

SCYL2-related autosomal recessive neurodevelopmental disorders: Arthrogryposis multiplex congenita-4 and beyond?

SCY1-like protein 2 (SCYL2) is a member of the SCY1-like pseudokinase family which regulates secretory protein trafficking. It plays a crucial role in the nervous system by suppressing excitotoxicity in the developing brain. Scyl2 knockout mice have excess prenatal mortality and survivors show severe neurological dysfunction.

Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A.

Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life.

Discovery of pathogenic variants in EFEMP2 and RAG1 and undetectable fetal phenotype: A challenge of prenatal exome sequencing.

Background: Exome sequencing in prenatal context confronts with pathogenic variants associated with phenotypes that are not detectable prenatally.

Materials And Methods: A consanguineous couple was referred at 24 weeks of gestation for prenatal genetic investigations after ultrasonography findings including decreased fetal movements, hypoplastic male external genitalia, retrognathia, prefrontal edema, anomalies of the great vessels with pulmonary atresia and dilated tortuous aorta.

Result: Prenatal trio exome sequencing identified two homozygous likely pathogenic variants, i.

Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study).

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26).

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm).

Whole F8 gene sequencing identified pathogenic structural variants in the remaining unsolved patients with severe hemophilia A.

Background: No F8 genetic abnormality is detected in approximately 1% to 2% of patients with severe hemophilia A (HA) using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal.

Objectives: The study aimed to identify the causal variation in families with a history of severe HA for whom genetic investigations failed.

FOXG1 variants can be associated with milder phenotypes than congenital Rett syndrome with unassisted walking and language development.

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene.

Allelic heterogeneity in a patient with postzygotic MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

A case of mosaic MTOR-associated hemimegalencephaly and hypomelanosis of Ito, died at 33 probably because of sudden unexpected death in epilepsy. Assessment of the variant allele fraction (VAF) in different tissues postmortem showed high variability not correlated with clinical features, representing the most detailed assessment of VAFs in different tissues to date.

Early prenatal diagnosis of causative homozygous variants in ASCC1 in a fetus with cystic hygroma and additional homozygous variants of unknown significance associated with a neurological phenotype not visible in early gestation: Dual diagnosis or not?

A consanguineous couple was referred at 10 weeks of gestation (WG) for prenatal genetic investigations due to isolated cystic hygroma. Prenatal trio exome sequencing identified causative homozygous truncating variants in ASCC1 previously implicated in spinal muscular atrophy with congenital bone fractures. Prenatal manifestations in ASCC1 can usually include hydramnios, fetal hypo-/akinesia, arthrogryposis, contractures and limb deformities, hydrops fetalis and cystic hygroma.

Walking test outcomes in adults with genetic neuromuscular diseases: a systematic literature review of their measurement properties.

Introduction: Neuromuscular diseases (NMDs) include a large group of heterogeneous diseases. NMDs frequently involve gait disorders, which affect quality of life. Several walking tests and tools have been described in the literature, but there is no consensus regarding the use of walking tests and tools in NMDs or of their measurement properties for walking outcomes.

Further description of two individuals with de novo p.(Glu127Lys) missense variant in the ASCL1 gene.

Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.

Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.

Purpose: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.

Methods: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.