Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (MRXSHG).

The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) encompasses a spectrum of neurodevelopmental disorders characterized by intellectual disability (ID), language/speech delay, attention issues, and epilepsy. These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting CNKSR2, a gene located at Xp22.12.

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease.

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease.

Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in (mcEDS-).

Background: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in (mcEDS-) or (mcEDS-). Although 48 patients in 33 families with mcEDS- have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.

Methods: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS- through international collaborations.

Lessons from a 30 year follow-up of monozygotic twins with discordant phenotype due to a ring 13 chromosomal mosaicism in one of them.

At the 43rd annual meeting of the ASHG in 1993, the senior author reported monozygotic twins with discordant phenotype due to a ring 13 chromosomal mosaic syndrome in one of them. Her major manifestations included: intrauterine growth restriction (IUGR), failure to thrive (FTT), delayed developmental milestones/intellectual disability (DDM/ID), left hemihypoplasia of her body with leg length discrepancy, left profound deafness due to inner ear malformation, telecanthus, dental anomalies mainly on the left side, congenital torticollis due to Klippel-Feil anomaly, 13 ribs, scoliosis, dislocation of the left hip, and distinctive left hand and feet. A blood karyotype at age 3 was normal.

Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1.

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation.

Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient's phenotype was complicated by a dual diagnosis.

Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades.

Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800).

Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance.

Gorlin syndrome, also known as Nevoid Basal-Cell Carcinoma Syndrome (NBCCS), is an autosomal dominant tumor predisposition syndrome that presents early in life with characteristic congenital malformations and tumors. This syndrome most commonly results from germline mutations of the PTCH1 tumor suppressor gene, which shows high penetrance and great intra and interfamilial phenotypic variability, as well as the SUFU tumor suppressor gene. Recently, the PTCH2 gene has also been implicated as a cause of Gorlin syndrome.

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features.

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders.

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase.

Novel De Novo EFTUD2 Mutations in 2 Cases With MFDM, Initially Suspected to Have Alternative Craniofacial Diagnoses.

We report 2 cases of mandibulofacial dysostosis with microcephaly (MFDM) with different and novel de novo mutations in the elongation factor Tu GTP binding domain containing 2 gene. Both cases were initially thought to have alternative disorders but were later correctly diagnosed through whole-exome sequencing. These cases expand upon our knowledge of the phenotypic spectrum in patients with MFDM, which will aid in defining the full phenotype of this disorder and increase awareness of this condition.

Schaaf-Yang syndrome overview: Report of 78 individuals.

Schaaf-Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader-Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2.

New ocular finding in Baraitser-Winter syndrome (BWS).

Baraitser-Winter syndrome was first described as a syndrome of iris coloboma, ptosis, hypertelorism, and mental retardation (Baraitser and Winter 1988; Baraitser, 2016). The phenotypic spectrum has since broadened to include other facial dysmorphic features, deafness, microcephaly, lissencephaly, and CNS findings (Baraitser and Winter 1988; Ganesh et al., 2005; Henedy et al.

RAF1 variants causing biventricular hypertrophic cardiomyopathy in two preterm infants: further phenotypic delineation and review of literature.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial features, short neck, short stature, congenital heart defects, pectus deformities, and variable developmental delays. NS is genetically heterogeneous as pathogenic variants in several genes involved in the Ras/mitogen-activated protein kinase pathway have been associated with a NS phenotype. Overall, 50% of patients harbor pathogenic variants in PTPN11, whereas 3-17% of patients have variants in RAF1.

Neonatal mucolipidosis type II alpha/beta due to compound heterozygosity for a known and novel mutation, and a concomitant heterozygous change in inherited from the mother.

We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogenic variant.

Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia.

Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype.

Identification of large NF1 duplications reciprocal to NAHR-mediated type-1 NF1 deletions.

Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial.

Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.

We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.