Focal cortical dysplasia (FCD) is a malformation of cortical development found in almost half of children referred for epilepsy surgery, making it the most frequent known cause of intractable focal epilepsy.¹ The histopathologic changes that define FCD type 2 (FCD2) include cortical dyslamination and large dysmorphic neurons without (type 2a) or with (type 2b) balloon cells.² Functional defects in the phosphatidylinositol 3-kinase (PI3K)–AKT (serine/threonine kinase, also known as protein kinase B)–mammalian target of rapamycin (mTOR) pathway have been demonstrated by Western blot, immunohistochemical staining, and AKT kinase and RNA expression analyses,^3-5 and mutations of DEPDC5 (OMIM 614191), PTEN (germline) (OMIM 601728), and PIK3CA (postzygotic or mosaic) (OMIM 171834) have been found in FCD, classified as FCD1 or FCD2.^3,6-13 Furthermore, 3 previous studies^14-16 reported mosaic mutations in MTOR in patients with FCD2. Many studies^2,3,6,17-19 have found links among diffuse megalencephaly, hemimegalencephaly, and FCD2, which have historically been considered distinct disorders. A link is further supported by discovery of germline or mosaic mutations of the same genes in the PI3K-AKT-mTOR pathway in patients with megalencephaly, hemimegalencephaly, or FCD. These data suggest that further genetic studies of FCD, as well as hemimegalencephaly and megalencephaly, are warranted to define additional genetic causes and explore links between the phenotypes and the levels and distribution of mosaic mutations.

Key Points: Autosomal-dominant SAMD9L gain-of-function mutations predispose to myeloid malignancies involving chromosome 7 aberrations. Hematopoietic reversions frequently occur postnatally and are associated with milder disease manifestations.

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor‐β (TGF‐β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF‐β signaling. More recently, TGF‐β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF‐β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF‐β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Significance: The relevance of transcription factor 7-like 1 (TCF7L1) during hypothalamo–pituitary (HP) axis development remains unknown. Using mouse genetics, we show that TCF7L1 acts as a transcriptional repressor to regulate the expression of the hypothalamic signals involved in pituitary formation. In addition, we screened a cohort of human patients with forebrain and/or pituitary defects and report two independent missense variants, p.R92P and p.R400Q, in human TCF7L1. Functional studies in vitro and rescue experiments in zebrafish mutants deficient for tcf7l1a and tcf7l1b show that the p.R92P and p.R400Q variants exhibit reduced repressing activity compared with wild-type TCF7L1. In summary, we identify TCF7L1 as a determinant for the establishment of HP axis development and as a potential candidate gene to be mutated in congenital hypopituitarism.