Refining the phenotype of SINO syndrome: A comprehensive cohort report of 14 novel cases.

Purpose: Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants.

Methods: In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form.

Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations.

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear.

Intellectual disability syndrome associated with a homozygous founder variant in in Ashkenazi Jews.

Background: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.

An Interdisciplinary Approach to Müllerian Outflow Tract Obstruction Associated with Cloacal Malformation and Cloacal Exstrophy.

People with cloacal malformation and 46,XX cloacal exstrophy are at risk of developing Müllerian outflow tract obstruction (OTO). Management of OTO requires expertise of many medical and surgical specialties. The primary presenting symptom associated with OTO is cyclical and later continuous pain and can be initially quelled with hormonal suppression as a temporizing measure to allow for patient maturation.

Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline.

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice.

TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis.

Telomerase catalyzes chromosome end replication in stem cells and other long-lived cells. Mutations in telomerase or telomere-related genes result in diseases known as telomeropathies. Telomerase is recruited to chromosome ends by the ACD/TPP1 protein (TPP1 hereafter), a component of the shelterin complex that protects chromosome ends from unwanted end joining.

Trainee perspectives of COVID-19 impact on medical genetics education.

Purpose: The SARS-CoV-2 pandemic abruptly altered medical education and clinical care. This work evaluates trainee perspectives of the impact of the pandemic on medical genetics education.

Methods: A Qualtrics survey was sent to physician trainees who rotated in genetics before or midpandemic.

Missense variant contribution to USP9X-female syndrome.

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome.

Author Correction: Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown.

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers.

Development of a decision support tool in pediatric Differences/Disorders of Sex Development.

Decisions about how best to clinically care for young children born with Disorders of Sex Development (DSD) can be challenging because some decisions are irreversible, have lasting physical and mental health effects, and are frequently made before the affected person is able to participate in decision-making. This multi-stage study involved (1) the development of a web-based decision support tool (DST) for parents of infants or young children and the clinicians caring for them; (2) the assessment of communications and decision making between DSD specialists and parents both before and after introduction of the DST; and (3) interviews with a broad range of stakeholders regarding optimizing the DST and integrating it into usual care. Experience over the course of the 3 stages of this research suggests the need for further refinement of the DST to increase acceptability to all stakeholder groups, the necessity to address misperceptions by providers that they are already accomplishing all aspects of SDM in regular care without a DST and misunderstandings by parents that decisions are unnecessary because only a single option is apparent, and to better incorporate the tool into regular clinic workflow.

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Background: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate.

Methods: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES.

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.

Context: 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS).

Objective: To report a gene for 46,XY GD etiology, especially for ETRS.

Design: Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing.

Genome-wide chromatin accessibility and transcriptome profiling show minimal epigenome changes and coordinated transcriptional dysregulation of hedgehog signaling in Danforth's short tail mice.

Danforth's short tail (Sd) mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10 000 live births. Sd animals exhibit aberrant axial skeleton, urogenital and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, vertebral-anal-cardiac-tracheo-esophageal fistula-renal-limb (VACTERL) association and persistent cloaca. Previous studies have shown that the Sd mutation results from an endogenous retroviral (ERV) insertion upstream of the Ptf1a gene resulting in its ectopic expression at E9.

Does Patient-centered Care Change Genital Surgery Decisions? The Strategic Use of Clinical Uncertainty in Disorders of Sex Development Clinics.

Genital surgery in children with ambiguous or atypical genitalia has been marred by controversies about the appropriateness and timing of surgery, generating clinical uncertainty about decision making. Since 2006, medical experts and patient advocates have argued for putting the child's needs central as patient-centered care. Based on audio recordings of 31 parent-clinician interactions in three clinics of disorders of sex development, we analyze how parents and clinicians decide on genital surgery.

High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype.

In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype.

Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability.

Intellectual disability (ID) affects up to 2% of the population world-wide and often coincides with other neurological conditions such as autism spectrum disorders. Mutations in cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID. encodes a histone demethylase for di- and tri-methylated histone H3 lysine 4 (H3K4me2/3), which are enriched in transcriptionally engaged promoter regions.

Interstitial lung disease of infancy caused by a new mutation.

Patients with personal or family history of congenital hypothyroidism, and/or neurological findings that also have chronic respiratory symptoms may have a mutation in the NKX2.1 gene as the unifying cause of their disease. Brain-lung-thyroid disease is the ensuing condition, which although rare, needs to be part of the differential diagnosis

Disorders of sex development (DSD): Clinical service delivery in the United States.

Following the principles of care recommended in the 2006 Consensus Statement on Disorders of Sex Development (DSD), along with input from representatives of peer support and advocacy groups, this study surveyed DSD clinical management practices at healthcare facilities in the United States. DSD are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. Facilities providing care for patients with DSD were targeted for participation.