The recently delineated KDM2B-associated neurodevelopmental disorder (NDD) is characterized by developmental delay and variable co-morbidity. Genotype-phenotype correlations are emerging, in particular a distinct clinical presentation caused by CxxC domain variants. We report here a novel intragenic deletion which leads to invitro expression of a shortened KDM2B protein lacking the complete CxxC domain. In addition, we present data on 12 other individuals; two with larger 12q24.31 microdeletions, one with a frameshift variant, and nine with missense variants. We analyzed genotype-phenotype correlations of this cohort combined with previously reported individuals (n = 68) and classify 37 variants in 47 individuals as pathogenic or likely pathogenic. We observe a highly penetrant CxxC-related phenotype with distinct facial features supported by GestaltMatcher. In contrast, our findings point to variable expressivity and incomplete penetrance of loss-of-function variants and JmjC domain variants complicating variant classification and genetic counseling. We identify KDM2B as a strong contributor to the 12q24.31 microdeletion syndrome, while also addressing the role of additional genes in the region. Thus, our study defines the KDM2B-NDD's clinical spectrum and highlights the importance of integrating molecular, (epi)genetic, and phenotypic data in NDD diagnostics.

FUZ, a component of the CPLANE (ciliogenesis and planar polarity effector) complex, regulates primary ciliogenesis. Five patients of various types of skeletal dysplasia with biallelic FUZ variants have been reported to date, yet the gene-disease relationship has not been established. Here, we report a patient with ciliopathy with a novel homozygous missense variant in FUZ. This patient shares phenotypes with all the previously reported patients and presents with novel phenotypes: aorto-pulmonary window (AP window) and Hirschsprung disease. These phenotypes can be explained by the inhibition of neural crest cell migration due to abnormal Sonic hedgehog (Shh) signaling caused by primary cilia dysfunction. In silico three-dimensional structural analysis predicted that the variant alters interactions between FUZ and CPLANE2 (RSG1), potentially disrupting ciliogenesis. This report provides additional evidence for FUZ as a causative gene for ciliopathy, offering novel insights into the phenotype spectrum and molecular mechanisms of FUZ-related ciliopathy.

Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-related phenotypes remains incompletely defined. This study systematically reviewed the clinical and genetic features of 10 Chinese patients harboring various TRPV4 variants. In the cohort, six patients were diagnosed with spondylometaphyseal dysplasia Kozlowski type (SMDK) and four patients with metatropic dysplasia (MD). The most common features involved spinal deformity (platyspondyly, kyphosis or scoliosis), and lower-limb malalignments (genu varum, genu valgum, or leg-length discrepancy). Two patients with MD had neurological deficits. The R594H and P799R substitutions were the most recurrent variants in our study. A novel variant (c.1628T>G, p.L543R) in the S2-S3 loop was identified. The study seeks to improve diagnostic precision by combining genetic and radiographic assessment, and highlights the importance of early spinal surveillance and multidisciplinary care to prevent neurological complications underlying TRPV4-mediated disorders.

We report a novel SCN5A missense variant (c.655C>T (p.Arg219Cys)) in a family with non-dilated left ventricular cardiomyopathy, broadening the spectrum of SCN5A-related structural cardiac diseases. The proband, a 35-year-old man, presented with embolic stroke and myocardial fibrosis in the absence of ventricular dilation. He exhibited a significant arrhythmic burden, including premature ventricular complexes and a non-sustained ventricular tachycardia, prompting prophylactic subcutaneous defibrillator implantation. Genetic testing identified a heterozygous SCN5A variant, also present in five relatives with myocardial fibrosis of variable extent on cardiac magnetic resonance imaging. The variant affects a highly conserved residue within the voltage-sensing domain of the Nav1.5 channel and, according to ACMG criteria, is best classified as a variant of uncertain significance. Nevertheless, its segregation with disease and the established functional importance of this region of Nav1.5 suggest a possible role in the observed phenotype. This report highlights a structural cardiomyopathy phenotype potentially linked to SCN5A dysfunction and supports the growing recognition of overlap between ion channelopathies and cardiomyopathies.

A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macrocephaly, post-axial polydactyly, developmental delay, autistic features and a series of craniofacial, brain, cardiac, ocular, and renal anomalies. Here, we describe two unrelated female probands with the known recurrent MAX variant, c.179G>A p.(Arg60Gln), who presented with the emerging phenotypes of the MAX-associated syndrome. We also propose that genitourinary abnormalities, including Mayer-Rokitanski-Kuster-Hauser syndrome in one individual, may constitute an expansion of the known phenotype. These findings contribute to the current knowledge regarding the phenotypic spectrum of MAX-associated polydactyly-macrocephaly syndrome.

Marbach-Schaaf neurodevelopmental syndrome (MASNS) is an ultra-rare, monogenic disease caused by pathogenic variation in PRKAR1B, which codes for the R1β regulatory subunit of protein kinase A (PKA), a key effector of cAMP signaling within the nervous system. This work provides a comprehensive clinical description of 12 subjects with pathogenic PRKAR1B variants, including two individuals with a heterozygous deletion including PRKAR1B, supporting haploinsufficiency as a possible mechanism of disease. Phenotypic information was obtained by interview, using a systematic multi-dimensional questionnaire. Besides expanding the evidence for established MASNS phenotypes like developmental delay, ID, ASD, pain insensitivity, as well as mild dysmorphisms, we broaden the clinical spectrum through the description of new and underreported findings, in particular increased body weight. In addition, the presence of genomic deletions suggests dosage sensitivity of PRKAR1B, demonstrating that both sequence and copy number variants should be considered in diagnostic testing. This work gives valuable insight into the pathophysiology of MASNS and sets a framework upon which to design future mechanistic studies of PKA signaling in brain development.

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder marked by bone fragility and deformities. This study aimed to define the clinical and molecular characteristics of 21 OI patients from 15 unrelated Egyptian families. Most probands were analyzed by exome sequencing. In three consanguineous cases, variants were identified through SNP array-based homozygosity mapping followed by direct sequencing of a candidate gene. Genotype-phenotype correlations were additionally explored. Parental consanguinity was documented in 66.7% (10/15) of the total cohort and in 100% (8/8) of the families with autosomal recessive OI. Pathogenic or likely pathogenic variants were identified in 14 families, five of which were novel. A variant of uncertain significance was identified in the remaining family. COL1A1 and COL1A2 (n = 7) were the most commonly mutated genes, followed by CRTAP (n = 4), while variants in P3H1, WNT1, CREB3L1, and SEC24D were each identified in a single patient. The present study highlights the molecular heterogeneity of OI. In total, 15 distinct variants in seven OI-related genes were identified. We also report a particularly high number of OI lethal forms affecting 10 patients out of 21. The study adds further evidence for the utility of ES in the genetic diagnosis of OI, which facilitates counseling and personalized care.

This case highlights the complexity of diagnosing dual rare metabolic diseases and the importance of genetic testing in uncovering novel pathogenic variants. It has also contributed to expanding the clinical manifestation spectrum of B4GALT1-CDG, which is an ultra-rare disorder.

Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impact of expanding access to GS, we report our experience implementing CincyKidsSeq, a prospective study offering GS as a "proband-first" test. Participants of all ages with at least one symptom were referred by genetics or non-genetics healthcare providers, or alternatively, were self-referred from February 2024 to February 2025. This diverse referral structure was evaluated for diagnostic yield while maintaining clinical oversight through a hybrid model in which reportable variants are delivered through genetic providers. The overall diagnostic yield of GS on 313 participants was 22% in the unstratified cohort. Self-referred patients had a higher diagnostic yield (11/33; 33%), compared with patients referred by a non-genetics provider (27/98; 27%), or genetics provider (32/182; 18%). Self-referred individuals were older, more likely to be female, frequently test-naïve, and utilized fewer human phenotype ontology (HPO) terms (p value = 0.0016). Self-referral may serve as an effective and complementary pathway for improving access to GS. Empowering families to initiate GS may be a reasonable pathway for an alternative model for genetic service delivery.

SLC20A1 encodes the ubiquitously expressed phosphate transporter PiT1, a protein with roles extending beyond phosphate homeostasis to include regulation of proliferation, differentiation, apoptosis, and embryonic development. While heterozygous SLC20A1 variants have been associated with urinary tract malformations, the impact of biallelic loss-of-function was unknown. We report the first human case of a biallelic homozygous predicted loss of function variant in SLC20A1 (c.674_675delAA; p.K225TfsX34) in a child with multiple congenital anomalies including tetralogy of Fallot, unilateral renal agenesis, postaxial polydactyly, growth impairment, and developmental delay. PiT1 expression was decreased in fibroblasts of the proband. Transcriptome analysis of patient-derived fibroblasts suggests significant dysregulation of pathways critical for organogenesis, including PI3K-Akt, Wnt, MAPK, and BMP signaling. Population screening identified a carrier frequency of 1:432 among Ashkenazi Jewish individuals. Our findings expand the phenotypic spectrum of SLC20A1-related disease and provide evidence that biallelic PiT1 deficiency causes a previously unrecognized multisystem developmental disorder.