ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

UNASSIGNED: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome.
UNASSIGNED: This study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr).
UNASSIGNED: Our findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.

Allan-Herndon-Dudley\'s syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.

Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.

MEGDEL syndrome, a rare autosomal recessive disorder characterized by 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome, results from mutations in the SERAC1 gene. This case report explores the clinical presentation, diagnostic challenges, and genetic findings of an 11-year-old boy with MEGDEL syndrome at a tertiary care center in Saudi Arabia. The patient, born to consanguineous parents, presented with developmental delay, cerebral palsy, intellectual disability, and seizures. Diagnostic evaluation at 15 months revealed 3-methylglutaconic aciduria, and subsequent genetic testing through whole exome sequencing confirmed a rare homozygous deletion variant in the SERAC1 gene. The patient exhibited brain atrophy, tracheal stenosis, laryngomalacia, and skeletal abnormalities. The complexity of MEGDEL syndrome manifestations and the challenge of distinguishing it from other metabolic disorders are discussed, emphasizing the significance of genetic testing in confirming the diagnosis. This case underscores the occurrence of MEGDEL syndrome in a child with cerebral palsy, highlighting the importance of a multidisciplinary approach for diagnosis and the need for genetic counseling in consanguineous families. Although the management remains primarily supportive, the report calls for more comprehensive epidemiological studies to determine the prevalence and incidence of MEGDEL syndrome. The findings contribute to the growing understanding of this rare disorder, thus emphasizing the necessity for ongoing research to enhance diagnostic accuracy and management strategies.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.

Glycosylation is the most common protein and lipid post-translational modification in humans. Congenital disorders of glycosylation (CDG) are characterized by both genetic and clinical heterogeneity, presenting multisystemic manifestations, and in most cases are autosomal recessive in inheritance. The PIGN gene is responsible for the addition of phosphoethanolamine to the first mannose in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, a highly conserved process that enables proteins to bind to the cell surface membrane. Here, we report a family with two siblings pediatric cases with the exact same compound heterozygous variants in PIGN. The (c.776T > C) variant of uncertain significance (VUS) together with a known pathogenic variant (c.932T > G), resulting in clinical features compatible with PIGN-related conditions, more specific the CDG. This is the first time that PIGN variant c.776T > C is reported in literature in individuals with PIGN-congenital disorder of glycosylation (PIGN-CDG), and the current submission in ClinVar by Invitae® is specifically of our case. Detailed clinical information and molecular analyses are presented. Here, we show for the first time two affected siblings with one pathogenic variant (c.932T > G) and the c.776T > C VUS in trans. In honor of the family, we propose the name Bella-Noah Syndrome for disorder.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

UNASSIGNED: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients.
UNASSIGNED: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene.
UNASSIGNED: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database.
UNASSIGNED: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

UNASSIGNED: Okur-Chung neurodevelopmental syndrome (OCNDS; #617062) has been associated with heterozygous mutations in the CSNK2A1 gene (*115440) mapped on the chromosome\'s 20p13 region.
UNASSIGNED: The analysis was performed on a 2-year-old patient who was admitted to our genetic diseases evaluation center by his family with a complaint of hypotonia. We detected a heterozygous NM_177559.3 (CSNK2A1):c.1139_1140dupGG (p.Met381GlyfsTer32) variant in the CSNK2A1 gene from a whole-exome sequence analysis.
UNASSIGNED: The variant that we detected has not been reported in open-access databases to date, so it was evaluated as a novel likely pathogenic variant according to the ACMG-2015 criteria. No variant was detected upon segregation analysis of the patient\'s parents; therefore, the related variant was evaluated as de novo. In this study, we offer the first report of a pathogenic frameshift variant in the CSNK2A1 gene that has a relationship with OCNDS.