Ria Garg

T‐complex protein 1 ( TCP1 ) encodes the TCP1α subunit, one of eight subunits of the chaperonin containing TCP1 ring complex (TRiC). Heterozygous TCP1 variants cause autosomal dominant neurodevelopmental disorder characterized by developmental delay or intellectual disability, seizures, pyramidal or cerebellar signs, and brain malformations, particularly polymicrogyria. However, the reported clinical spectrum remains limited. We report a 4‐year‐old girl with global developmental delay, speech and motor delay, behavioral dysregulation, microcephaly, hypotonia with core weakness, and a previously unreported heterozygous likely pathogenic TCP1 variant, c.1392delT (p.A465Qfs*3). This frameshift variant is located in exon 11, truncates the final 16.5% of the protein, is predicted to undergo nonsense‐mediated decay, and is absent from gnomAD. Biological parental testing was unavailable, precluding determination of variant inheritance. Brain magnetic resonance imaging (MRI) demonstrated an absent septum pellucidum with mild bilateral frontal sulcation/gyration asymmetry without polymicrogyria; the optic nerves and pituitary were normal. No seizures were documented through age 4 years. Additional findings included bicuspid aortic valve with mild aortic insufficiency, asthma, severe eczema/atopy, and multiple food allergies. This case suggests that the molecular and neuroimaging spectrum of TCP1 ‐related neurodevelopmental disorder may be broader than previously recognized; however, a causal association between TCP1 and absent septum pellucidum cannot be established from a single case. The relationship of the cardiac and atopic findings to TCP1 remains uncertain. Additional cases and functional studies are needed to clarify genotype–phenotype relationships.

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Börjeson–Forssman–Lehmann syndrome (BFLS) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the plant homeodomain finger protein 6 ( PHF6 ) gene. Core features include developmental delay, intellectual disability, dysmorphic craniofacial characteristics, obesity, hypogonadism and digital anomalies. Orofacial clefting has not been recognised as part of the canonical phenotype and is rarely reported in association with BFLS. One cohort study listed cleft lip and/or palate as an uncommon feature without individual case details, and a separate report described a female with a nonsense PHF6 variant and clefting of the hard and soft palate. Here, we describe a BFLS female with a de novo missense PHF6 variant who presented with cleft palate. This case adds to the emerging evidence that clefting, though uncommon, may be a recurrent manifestation. It supports the inclusion of PHF6 in the genetic testing of patients presenting with syndromic orofacial clefting when accompanied by neurodevelopmental delay or dysmorphism.

Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable associations with skeletal and neurodevelopmental abnormalities. Duplication of the near-complete, isolated PAR1 with a comprehensive clinical description has not been reported. Case Presentation: We report a male patient with a 2.49 Mb duplication encompassing nearly the entire PAR1 region (chrX:200854–2692897, GRCh37). Clinical features included global developmental delay (GDD), autism spectrum disorder (ASD), recurrent seizures, hypotonia with joint hypermobility, dysmorphic features, and proportionate tall stature. The duplicated segment contains 30 genes, including 15 protein-coding genes that escape X-inactivation. Among these, SHOX, DHRSX, ASMT, and CSF2RA are notable candidates contributing to the observed phenotype. Conclusions: This report presents a detailed clinical characterization of a rare, near-complete, isolated PAR1 duplication in a male individual. The co-occurrence of tall stature, GDD, ASD, and seizures raises the possibility of a dosage-related phenotypic effect involving one or more genes within the duplicated interval. While causality cannot be definitively established, these observations contribute to the emerging understanding of the functional consequences of Xp22.33 duplications and suggest that increased copy number within this region may be associated with a clinically significant neurodevelopmental phenotype.

Background: Chromosome 19 is the most gene-dense chromosome in the human genome, with a high frequency of segmental duplications that predispose it to genomic rearrangements. While deletions of chromosome 19 have been associated with various clinical conditions, duplications remain poorly characterised. Here, we report three cases involving 19p13.11 duplication and describe the associated clinical phenotype. Methods: We describe three unrelated individuals with microduplications at 19p13.11 identified either via clinical whole-exome sequencing or chromosomal microarray. The probands underwent detailed clinical genetic evaluations, and CNVs were confirmed with parental testing when available. Sequencing reads were aligned to the GRCh37/hg19 human genome build. Results: All three probands exhibited neurodevelopmental delays, attention-deficit/hyperactivity disorder and speech delay. Additional overlapping features included joint hypermobility, short stature and craniofacial anomalies. Patient-specific manifestations included haematological abnormalities, musculoskeletal asymmetries and cardiac findings. Duplicated regions spanned 1.2–1.6 Mb and encompassed 41–49 protein-coding genes. Patients 2 and 3 have CNVs that overlap 76% with those of Patient 1. Several genes have predicted high triplosensitivity scores and are associated with autosomal dominant neurodevelopmental and skeletal disorders. Patient 1, with the largest duplication, had more extensive systemic involvement, likely reflecting the broader gene dosage effect. Conclusion: This is the first comprehensive clinical and molecular characterisation of 19p13.11 duplications, suggesting a recurring multisystem phenotype driven by gene dosage sensitivity. These findings support the inclusion of 19p13.11 duplications in diagnostic evaluations for neurodevelopmental and multisystem disorders.

The zinc finger homeobox 3 ( ZFHX3 ) gene encodes a transcription factor involved in neurodevelopment and organogenesis. ZFHX3 haploinsufficiency is linked to intellectual disability, epilepsy and neurodevelopmental defects, but its potential involvement in neural tube defects (NTDs) and related structural anomalies is unknown. We report a female proband with a de novo heterozygous ZFHX3 variant (NM_006885.3: c.5876 A>C, p.(Gln1959Pro), identified via exome sequencing. She presented with spina bifida occulta, segmental spinal dysgenesis, bilateral clubfeet, bicuspid aortic valve and genital anomaly. This report suggests an expanded phenotypic spectrum of ZFHX3 -associated disorders. Given the known interactions of ZFHX3 with Wnt/β-catenin, mTOR and Hippo signalling pathways, we hypothesise that disruptions in these networks could contribute to NTDs and skeletal defects. No functional studies were performed, so causality cannot be established. Further research and reports of similar phenotypes in ZFHX3 variants are needed to confirm its role in NTDs and other congenital structural anomalies.

Nizon-Isidor syndrome (NIZIDS) is a rare neurodevelopmental disorder caused by heterozygous MED12L variants, where previously pathogenic single-nucleotide variants (SNVs) were only reported as de novo events. Here, we report the first case of maternally inherited MED12L nonsense variant in NIZIDS. Clinical assessment and family history evaluation revealed global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment. Exome sequencing (ES) of the proband and both parents confirmed the presence of a maternally inherited likely pathogenic MED12L nonsense variant in the proband. Additional pathogenic variants in GAMT (maternal) and TNFRSF13B (paternal) genes were also identified in the proband. The clinical history of the mother suggested variable expressivity of the MED12L variant. Our case report challenges the presumed de novo inheritance of MED12L SNVs and demonstrates variable expressivity, thereby highlighting the benefit of a complete phenotype-driven approach when analyzing exome and genome data.

ZC4H2 is an X-linked gene that has emerged as critical for neural development, synaptic functioning, and gene regulation. We present an 11-month-old male who was evaluated for bilateral congenital vertical talus identified in the newborn period. Exome sequencing identified a hemizygous, missense variant in ZC4H2, NM_018684.4:c.196C>T p.(Leu66Phe), that affects the same amino acid residue as a previously reported, pathogenic ZC4H2 variant, c.197T>A p.(Leu66His). The variant was inherited from his mother, who had camptodactyly of the fifth fingers, and was also present in the maternal uncle who carried a diagnosis of cerebral palsy. The pathogenic missense variant in this family is located in the coiled-coil domain of the ZC4H2 protein. Although data remain scarce, missense variants in this domain may be associated with a milder, ZC4H2-associated rare disorder (ZARD) phenotype.

Deletions within the chromosomal locus 1p31.1 are rare, with only a limited number of documented cases. The typical clinical presentation includes intellectual disability, failure to thrive, and craniofacial abnormalities. Some cases may also present with cardiac, gastrointestinal, and genitourinary malformations. Variability in deletion size contributes to a broad spectrum of clinical phenotypes, and a comprehensive understanding of the syndrome’s manifestations is still evolving. This case study aims to provide additional insights into 1p31.1 microdeletion syndrome, enhancing knowledge of its genetic and phenotypic characteristics to improve recognition by clinicians. Here, we report a case featuring a 14.385 Mb deletion isolated to the 1p31.1 region, encompassing 41 genes. The deletion manifested with microcephaly, distinctive facial morphology, hypotonia, developmental delay, bilateral cryptorchidism, and flat feet. Notably, our case also exhibited congenital thickening of the lingual and labial frenulum, a trait not typically associated with this deletion.

Background: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by impaired social communication and repetitive behaviours. The genetic basis of ASD is complex and involves both rare variants with large effect sizes and common variants with small effect sizes. Case presentation: This case report describes a 19-year-old male with ASD, intellectual disability, absent speech, and epilepsy. Molecular testing revealed a novel maternally inherited variant in the USP51 gene, which encodes Ubiquitin Specific Peptidase 51, a deubiquitinating enzyme involved in the DNA damage response. Conclusions: Based on current knowledge, the variant is predicted to result in a truncated protein and is considered a variant of uncertain significance (VUS). The USP51 gene has been implicated in neurodevelopment, and its role in the developing brain suggests its potential relevance to ASD. Further studies are needed to establish the association of USP51 variants with ASD and elucidate the full phenotypic spectrum associated with these variants.