Genetic variations in MID1 were initially identified as the cause of X-linked Opitz G/BBB syndrome, which is characterized by hypertelorism, hypospadias, and a high incidence of intellectual disability. However, increasing evidence has shown that MID1 mutations are associated with a broader spectrum of phenotypes, and the genotype-phenotype correlation remains unclear. In this study, the authors report a 4-year-old boy presenting with congenital unilateral nostril hypoplasia, preaxial polydactyly, hemispheric brain asymmetry, and moderate intellectual disability. Whole-exome sequencing identified a novel hemizygous missense variant in MID1 (c.1600G>T; p.Val534Leu), inherited from an unaffected heterozygous mother and also present in the proband's clinically normal sister. Functional analysis suggested that this variant may affect protein-protein interactions and microtubule-associated cellular processes. In addition, expression profiling revealed that MID1 is highly enriched in the central nervous system, supporting its essential role in neurodevelopment. Structural modeling with AlphaFold3 showed preservation of the overall protein fold, whereas DynaMut2 predicted local destabilization and increased hydrophobic packing near the variant site. The variant segregated in the family in an X-linked manner and was classified as possibly damaging by PolyPhen-2. In conclusion, our findings expand the mutational and phenotypic spectrum of MID1-related disorders and suggest a potential pathogenic role of this variant in neurodevelopmental and craniofacial abnormalities. Typical GLI3-related Greig cephalopolysyndactyly syndrome (GLI3-GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GLI3-GCPS and may be more common in individuals with large (>300 kb) deletions that encompass GLI3. Approximately 20% of individuals with GLI3-GCPS have hypoplasia or agenesis of the corpus callosum. The diagnosis of GLI3-GCPS is established in a proband with typical clinical findings and either a heterozygous pathogenic variant in GLI3 or a deletion of chromosome 7p14.1 involving GLI3 identified by molecular genetic testing. Treatment of manifestations: Elective surgical repair of polydactyly with greatest priority given to correction of preaxial polydactyly of the hands; for polydactyly of the feet, the cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications. Syndactyly that is more than minimal is typically repaired surgically. Occupational and physical therapy to improve motor skills; developmental and educational support as needed; standardized treatment for seizures as needed. Surveillance: Monitoring for evidence of increased rate of head growth or neurologic concerns and the need for brain MRI. Physical medicine and occupational and physical therapy assessments of mobility and self-help skills at each visit or as needed; assessment of developmental progress and educational needs at each visit or as needed; monitor those with seizures at each visit. GLI3-GCPS is inherited in an autosomal dominant manner. Some individuals diagnosed with GLI3-GCPS have the disorder as the result of a genetic alteration inherited from a parent. The proportion of individuals with GLI3-GCPS caused by de novo genetic alteration is unknown. If the causative genetic alteration in the proband is a chromosome 7p14.1 deletion, the parents of the proband are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents: if a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%; if a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables. Each child of an individual with GLI3-GCPS has a 50% chance of inheriting the causative genetic alteration. If the GLI3-GCPS-causing genetic alteration has been identified in an affected family member (or a balanced structural chromosome rearrangement involving 7p14.1 is identified in a parent), prenatal and preimplantation genetic testing are possible.

Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.

Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.

GLI family zinc finger proteins are transcriptional effectors of the sonic hedgehog signaling pathway. GLI regulates gene expression and repression at various phases of embryonic morphogenesis. In humans, 4 GLI genes are known, and GLI2 (2q14.2) and GLI3 (7p14.1) mutations cause different syndromes. Here, we present 2 distinctive cases with a chromosomal microdeletion in one of these genes. Patient 1 is a 14-year-old girl with Culler-Jones syndrome. She manifested short stature, cleft palate, and mild intellectual/social disability caused by a 6.6-Mb deletion of 2q14.1q14.3. Patient 2 is a 2-year-old girl with Greig cephalopolysyndactyly contiguous gene deletion syndrome. She manifested macrocephaly, preaxial polysyndactyly, psychomotor developmental delay, cerebral cavernous malformations, and glucose intolerance due to a 6.2-Mb deletion of 7p14.1p12.3 which included GLI3, GCK, and CCM2. Each patient manifests a different phenotype which is associated with different functions of each GLI gene and different effects of the chromosomal contiguous gene deletion. We summarize the phenotypic extent of GLI2/3 syndromes in the literature and determine that these 2 syndromes manifest opposite features to a certain extent, such as midface hypoplasia or macrocephaly, and anterior or posterior side of polydactyly. We propose a GLIA/R balance model that may explain these findings.