Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein.

PURPOSE: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

Mandibular-pelvic-patellar syndrome is a novel PITX1-related disorder due to alteration of PITX1 transactivation ability.

PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1-TBX4-SOX9 signaling pathway.

The different clinical facets of SYN1-related neurodevelopmental disorders.

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome.

Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy. Three genes, BUB1B, CEP57 and TRIP13, are involved in this syndrome. Only 7 patients carrying pathogenic variants in CEP57 are reported to date. Here we report two adult brothers born to Moroccan related parents, who presented with intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, learning disabilities, skeletal anomalies with thumb hypoplasia and dental abnormalities. Both brothers have mosaic variegated aneuploidies on blood karyotype. A previously reported homozygous 11 bp duplication was identified in CEP57 in the two brothers. We propose that a FoSTeS (Fork Stalling and Template Switching) mechanism could be involved in the occurrence of this duplication. This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly.