BACKGROUND Congenital hypoplasia of the thumb type IV, also known as floating thumb, is a condition in which 2 small phalanges are attached to the hand with a thin skin bridge. Surgical management options for this condition vary from amputation to flap reconstruction. MATERIAL AND METHODS This retrospective study analyzed 11 infants with congenital hypoplasia of the thumb type IV who underwent surgical reconstruction using a modified vascularized polydactylous hallux flap. The study included 6 male and 5 female infants, aged 6 to 24 months. Functional evaluations and radiographic studies were conducted postoperatively. RESULTS All 11 patients underwent the complete surgical protocol. Successful vascular and nerve anastomoses were performed during the initial procedure, ensuring sufficient blood supply and neural connectivity to the transferred toes. The second operation showed promising outcomes, including improvements in thumb opposition, grasp strength, and overall function. Postoperative assessments demonstrated satisfactory radiographic alignment and no major complications during the follow-up period. CONCLUSIONS The modified vascularized polydactylous hallux flap reconstruction is a viable surgical option for managing congenital hypoplasia of the thumb type IV in infants. This technique effectively restores thumb opposition, grasp strength, and overall hand function, with satisfactory radiographic alignment and minimal complications. The study findings support the efficacy and safety of this surgical approach in addressing this rare congenital anomaly.

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

OBJECTIVE: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms.
METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4.
RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing.
CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis.
CONCLUSIONS: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

De novo germline variants of the SRY-related HMG-box 11 gene (SOX11) have been reported to cause Coffin-Siris syndrome-9 (CSS-9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS-like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio-based whole-exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein-coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high-mobility group [HMG] domain and non-HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS-9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.

Pathogenic variants of the KCNH1 gene can cause dominant-inherited Temple-Baraitser/Zimmermann-Laband syndrome with severe mental retardation, seizure, gingival hyperplasia and nail hypoplasia. This study established an induced pluripotent stem cell (iPSC) line using urinary cells from a girl with KCNH1 recurrent/hotspot pathogenic variant c.1070G > A (p.R357Q). The cell identity, pluripotency, karyotypic integrity, absence of reprogramming virus and mycoplasma contamination, and differential potential to three germ layers of the iPSC line, named as ZJUCHi003, were characterized and confirmed. Furthermore, ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons. This cell line will be useful for investigating the pathogenic mechanisms of KCNH1 variants-associated symptoms, as well as for evaluating novel therapeutic approaches.

Synaptotagmin-1 (SYT1) plays a pivotal role in regulating presynaptic processes, including neurotransmitter release. SYT1 variants perturb synaptic vesicle endocytosis and exocytosis, resulting in a series of neurodevelopmental disorders defined as Baker-Gordon syndrome. Herein, we report the case of a newborn with dysmorphic facial appearance, severe hypotonia, poor feeding, gastroesophageal reflux, and an inability to eat and breathe, diagnosed with Baker-Gordon syndrome. A retrospective search was performed on a newborn with Baker-Gordon syndrome. Medical charts were reviewed, with focus on the clinical presentation, diagnostic process, and treatment outcomes. Whole-genome high-throughput DNA sequencing was performed to identify genetic variants. Whole-exome sequencing identified the likely pathogenic variant as SYT1 C.551 T > C(p.V184A). Sanger sequencing results indicated that this variant was a de novo mutation in a conservative site located in the C2A domain of the protein. The patient died at 57 days old because of severe feeding and breathing problems. Our findings of a novel lethal variant in the C2A domain of SYT1 in the youngest patient diagnosed infantile Baker-Gordon syndrome who presented with the most severe hypotonia reported to date expands the spectrum of SYT1- associated neurodevelopmental disorders.

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BACKGROUND: Although the whole-exome sequencing (WES) approach has been widely used in clinic, many rare diseases with syndromic and nonsyndromic neurological manifestations remain undiagnosed. Coffin-Siris syndrome (CSS) is a rare autosomal dominant genetic disease characterized by neurodevelopmental delay. A suspected diagnosis can be made based on the typical CSS clinical features; however, molecular genetic testing is necessary for a confirmed diagnosis.
OBJECTIVE: Three CSS-like patients with negative results in the WES and chromosomal microarray analysis (CMA) were recruited in this study.
METHODS: We used whole-genome sequencing (WGS) technology to sequence the peripheral blood of the three families. To further explore the possible pathogenesis of CSS, we performed RNA-sequencing (RNA-seq).
RESULTS: WGS identified the three CSS patients were carrying de novo copy number variants of the ARID1B gene, which have not been reported before. RNA-seq identified 184 differentially expressed genes (DEGs), with 116 up-regulated and 68 down-regulated. Functional annotation of DEGs showed that two biological processes (immune response, chemokine activity) and two signaling pathways (cytokine-cytokine receptor interaction, chemokine activity) were highlighted. We speculated that ARID1B deficiency might trigger abnormal immune responses, which may be involved in the pathophysiologic mechanisms of CSS.
CONCLUSIONS: Our research provided further support for WGS application in CSS diagnosis and made an investigational approach for the underlying mechanisms of CSS.