Muthusamy, Karthik

ABSTRACT The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5‐year‐old boy with classical cohesinopathy features, including DD/ID and feeding difficulties, along with non‐classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel de novo missense variant of uncertain significance (NM_005862.3:c.643G>A(p.Val215Ile)) in the STAG1 gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other STAG1 variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1‐RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1‐related cohesinopathy and advances our understanding of the disease mechanism.

ABSTRACT MYH11 ‐related hereditary type 2 visceral myopathy is a rare smooth muscle disorder typically presenting in infancy with severe gastrointestinal and genitourinary dysfunction. We describe a 73‐year‐old female with lifelong symptoms of gastrointestinal and urinary dysfunction, including chronic constipation, neurogenic bladder, recurrent urinary tract infections, gastroparesis, and pelvic organ prolapse. A multigenerational family history revealed similar visceral smooth muscle abnormalities among 14 affected individuals over five generations, suggesting autosomal dominant inheritance. Whole‐genome sequencing identified a heterozygous, likely pathogenic variant in MYH11 c.5819del; p.(Pro1940HisfsTer91), consistent with the diagnosis of autosomal dominant type 2 visceral myopathy. This variant causes production of an abnormally elongated myosin‐heavy chain, disrupting muscle contractile function. This individual's survival into her eighth decade reflects long‐term clinical stability, possibly attributable to the variant's milder effect. We describe the clinical course of the disease, along with a comprehensive review of previously described individuals with the same variant. This case broadens the phenotypic spectrum of MYH11 ‐associated visceral myopathy, demonstrating that late‐onset, milder forms can occur and remain compatible with long‐term survival with optimal supportive management. Comprehensive genetic evaluation identifies primary disorders, enabling precise diagnosis, tailored management, and informed genetic counseling for complex phenotypes.

ABSTRACT Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1 , which encodes glycogenin‐1. It is characterized by progressive muscle weakness and PAS‐positive, diastase‐resistant polyglucosan inclusions on muscle biopsy. We report a 64‐year‐old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice‐site variant, NM_004130.4( GYG1 ):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4( GYG1 ):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA‐seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long‐range PCR results were inconclusive. Long‐read GS definitively demonstrated that the two variants were in trans , establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult‐onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA‐seq, and long‐read GS for resolving complex phasing challenges.

ABSTRACT The TLK2 gene encodes a serine/threonine kinase essential for chromatin assembly. Loss‐of‐function heterozygous variants were recently identified as a cause of a rare neurodevelopmental disorder ( TLK2 ‐NDD) characterized by a variable spectrum of developmental delay, autism, behavioral issues, and severe constipation. We describe two unrelated young adult females presenting with neurodevelopmental delay, neurobehavioral abnormalities, and constipation since infancy secondary to truncating TLK2 variants. Case 1 is a 26‐year‐old female who was referred to our clinic for extended assessment of new‐onset psychosis and concern for seizures. She has been diagnosed with autism spectrum disorder and has a history of developmental delay, constipation, and aggressive outbursts since early childhood. At the age of 24 years, she developed an acute onset of persistent daily auditory hallucinations with threatening content that was refractory to medical and electroconvulsive therapy. Video‐ EEG assessment found no correlates for hallucinations. Trio whole genome sequencing revealed a heterozygous de novo pathogenic TLK2 variant, NM_006852.6:c. 367C >T (p. Arg123Ter ). Case 2 is a 19‐year‐old female who was evaluated for developmental delay and intellectual disability. Her phenotype was also notable for constipation since infancy and suggestive hypothalamic features with obesity, metrorrhagia, and hypersomnia. Trio whole genome sequencing revealed a likely pathogenic heterozygous TLK2 variant NM_006852.6:c.587del(p.Ser196ThrfsTer19) inherited from an asymptomatic, mosaic father. We present the adult phenotype of two young females with truncating variants in TLK2 and unusual phenotypic features of refractory hallucinations and possible hypothalamic syndrome. While both features may be independent of TLK2 ‐NDD, evidence from schizophrenia genome‐wide association studies and tissue expression data indicates that these features might be a part of longitudinal phenotype development. Long‐term follow‐up studies are required to unfold the phenotypic spectrum of TLK2 ‐NDD and to better understand the implications of these findings for management and prognosis.

ABSTRACT LYRM7‐associated mitochondrial complex III deficiency has classically been described in the literature as a childhood‐onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent‐onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult‐onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult‐onset isolated acute optic neuropathy can be a manifestation of LYRM7‐related mitochondrial disorder. LYRM7‐associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para‐ and post‐infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra‐and inter‐familial variability seen with this rare disorder.