Phenotype Expansion of Malan Syndrome: New Cases and a Review of the Literature

American Journal of Medical Genetics Part A · 2026-04-03

Malan syndrome is an ultra-rare overgrowth syndrome caused by pathogenic variants or deletions in nuclear factor one X (NFIX) located at 19p13.2. Here, we report a comprehensive literature review and phenotyping of known patients with Malan syndrome and present a novel cohort of eight patients. This report further establishes the common characteristics of Malan syndrome, expands the ophthalmologic features and airway distress phenotypes, and provides updated management recommendations.

A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

Current Biology · 2025-02-20 · 9 citations

<h2>Summary</h2> The cohesin protein complex is essential for the formation of topologically associating domains (TADs) and chromatin loops on interphase chromosomes.¹^,²^,³^,⁴^,⁵ For the loading onto chromosomes, cohesin requires the cohesin loader complex formed by NIPBL⁶^,⁷^,⁸ and MAU2.⁹ Cohesin localizes at enhancers and gene promoters with NIPBL in mammalian cells¹⁰^,¹¹^,¹²^,¹³^,¹⁴ and forms enhancer-promoter loops.¹⁵^,¹⁶ Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous disorder affecting multiple organs and systems during development,¹⁷^,¹⁸ caused by mutations in the cohesin loader <i>NIPBL</i> gene (>60% of patients),¹⁹^,²⁰^,²¹^,²²^,²³ as well as in genes encoding cohesin, a chromatin regulator, BRD4, and cohesin-related factors.²⁴^,²⁵^,²⁶^,²⁷ We also reported CHOPS syndrome that phenotypically overlaps with CdLS²⁸^,²⁹ and is caused by gene mutations of a super elongation complex (SEC) core component, AFF4. Although these syndromes are associated with transcriptional dysregulation,²⁴^,²⁸^,³⁰^,³¹^,³² the underlying mechanism remains unclear. In this study, we provide the first comprehensive analysis of chromosome architectural changes caused by these mutations using cell lines derived from CdLS and CHOPS syndrome patients. In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3 (H3K27ac)³³^,³⁴^,³⁵ in most enhancers with enhancer-promoter loop attenuation. By contrast, TADs were maintained in both patient cells. These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes. These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping.

P398: An unusual cause of hexokinase 1 deficiency

Genetics in Medicine Open · 2025-01-01

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Nature Communications · 2025-02-17 · 2 citations

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

Rothmund‐Thomson Syndrome Type 2 in an African American/Puerto Rican Child Demonstrates Diagnostic Challenges in Diverse Population

American Journal of Medical Genetics Part A · 2025-06-09 · 1 citations

Rothumnd-Thomson syndrome (RTS) is a rare genetic condition characterized by poikiloderma, sparse hair, short stature, skeletal abnormalities, cataracts, and increased risk for malignancies. The presenting symptom is often a classic rash with erythema on the cheeks and face with spread to extensor surfaces of extremities. Gradually over months to years, this rash develops into poikiloderma (reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy). Identification of this characteristic rash may facilitate early diagnosis and management in patients with RTS; however, this may be more challenging in patients from diverse populations, especially with darker skin. Herein, we report an African-American/Puerto Rican 4-year, 11-month-old male who presented with feeding difficulties, scaly patches of skin, sparse hair, short stature, hypertelorism, and developmental delay. Initially, poikiloderma on his extremities was considered to be psoriasiform dermatitis. Exome sequencing revealed compound heterozygous pathogenic variants in the RECQL4 gene, c.1568_1573delGCCCCTinsCCCCC (p.Ser523fs) and c.2412_2420delGGCCGGGCG (p.Ala805_Arg807del) confirming a diagnosis of RTS type 2. This report underscores the risk of misdiagnosis or delayed diagnoses of RTS in diverse populations and highlights the importance of comprehensive molecular evaluation in diagnosing and managing rare conditions.

16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome

Genes · 2025-01-24 · 1 citations

Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development. Clinical report: Here, we report three individuals who present with clinical features of KBG syndrome. These individuals carry microdeletions encompassing only the non-coding exon 1 of ANKRD11 and its upstream region. Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients. Conclusions: We concluded that microdeletions involving non-coding exon 1 of ANKRD11 lead to KBG syndrome. Our study suggests the utility of transcriptome analysis in aiding the interpretation of novel copy number variants in the non-coding genomic region of ANKRD11.

Clinical Characteristics of Patients With Kabuki Syndrome at a Single Tertiary Children's Hospital

American Journal of Medical Genetics Part A · 2025-02-12 · 1 citations

Kabuki syndrome (KS) is a multisystem disorder characterized by facial dysmorphic features, growth delays, skeletal anomalies, and variable intellectual disability (ID) due to pathogenic variants in KMT2D and KDM6A. Significant phenotypic variability has been reported in patients with KS. To further characterize the variability observed in the genomic sequencing era, comprehensive genotypic and phenotypic information from 36 patients with KS and likely pathogenic or pathogenic KMT2D or KDM6A variants at the Children's Hospital of Philadelphia (CHOP) was collected. Dysmorphic features, growth restriction, and developmental delays were commonly reported, as expected. Hyperinsulinism (HI) was seen more frequently than in previously published cohorts. Patients diagnosed with HI were more likely to require neonatal intensive care unit admission and feeding tube(s). Intellectual disability was variable in severity and less frequent than previously reported. This study highlights the wide phenotypic spectrum of KS and expands our knowledge of the diagnostic process for KS. This study is limited by potential ascertainment bias as CHOP is a HI Center of Excellence, however, our cohort is unique as many were ascertained with disease-agnostic testing. Screening for hyperinsulinism, including consideration of diagnostic fast, at time of KS diagnosis is warranted to prevent long-term neurologic effects of untreated hypoglycemia.

An Unusual Cause of Hexokinase 1 Deficiency—Case Report

eJHaem · 2025-08-01

ABSTRACT Introduction Molecular analysis of red cell disorders has revolutionized diagnosis, however, there remain challenges. Main Symptoms This patient presented with hemolytic anemia in the newborn period. He required chronic transfusions to maintain his hemoglobin level until 6 years of age. A splenectomy was performed at 3 years of age. Main Diagnoses Using whole genome sequencing, we were able to identify a duplication upstream of the red cell promoter of HK1 . Long‐read RNA sequencing established aberrant expression off of this promoter. Conclusions These non‐coding variants remain challenging to identify. His promoter duplication may have a founder effect in South Asia.

P186: The earliest sign of hypogonadotropic hypogonadism: The importance of genetic screening and evaluation in individuals with microphallus

Genetics in Medicine Open · 2024-01-01

Microphallus is a congenital difference in male presenting individuals defined as a stretched penile length of less than 2.5 standard deviations (SDs) below the mean for age. As an anomaly affecting the genital system, this is a finding that meets criteria for a variation of sex characteristic/difference of sex development (VSC/DSD). Currently, 37 OMIM genes have microphallus as associations, most of which are related to Hypogonadotropic Hypogonadism (HH). HH can be defined as failure of the normal episodic GnRH secretion.

The Brain Gene Registry: a data snapshot

Journal of Neurodevelopmental Disorders · 2024-04-17 · 10 citations

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.