Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants inFOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part ofFOXC2.

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1-related disorders.

Background: Variants in the ryanodine receptor 1 (RYR1) gene have been linked to a range of disorders, from congenital myopathy to adult-onset manifestations, with phenotypes varying from mild to severe. Methods: A retrospective review was conducted on an Israeli cohort of 36 individuals with RYR1 variants, identified through genetic testing as part of a national collaboration among multiple pediatric and adult neuromuscular clinics. Clinical features, molecular data, laboratory results, electromyographic findings, and muscle histology were analyzed. Each variant was classified according to its respective domain within the RYR1 gene. Results: Thirty-six cases were included in the analysis; 31 were from 11 unrelated families, and 5 were sporadic. Nine individuals were asymptomatic with normal CK levels. Most of the 27 affected patients presented with variable degrees of perinatal weakness, often accompanied by respiratory impairment or arthrogryposis. Weakness was predominantly proximal, with clinical courses that included deterioration, improvement, or stabilization. Three cases of King–Denborough syndrome were identified. Additional presentations included malignant hyperthermia and, in isolated cases, periodic paralysis. Muscle biopsies demonstrated considerable histologic heterogeneity, including fiber-size variation, internal nuclei, multiminicores, and fibrosis or dystrophic features. The pathogenic RYR1 variants included five compound-heterozygous genotypes, two homozygous variants, and two heterozygous variants. There was a positive correlation between variants located in the Bsol domain and disease severity. Conclusions: This cohort confirms and expands the clinical and histological diversity associated with RYR1 variants in Israel. Variants in the Bsol domain appear to be indicative of disease severity.

Background/Objectives: Pathogenic variants in collagen type 4 α5 chain (COL4A5), responsible for X-linked Alport syndrome, are classically associated with progressive kidney disease, sensorineural hearing impairment, and ocular abnormalities. Cerebrovascular involvement is not considered part of the COL4A5-related phenotype, although rare recent reports suggest it may occur. We describe a family with cerebrovascular events across three generations, segregating in a clear X-linked pattern, and evaluate whether these events could be linked to a pathogenic COL4A5 variant identified in the proband. Methods: We report the clinical, radiological, and genetic findings in a 16-year-old heterozygous female proband, interpreted in the context of her family’s cerebrovascular history. Exome sequencing, chromosomal microarray, and familial segregation analysis were performed. Results: The proband presented with severe migraine, cerebellar microhemorrhage, and poor visualization of the left distal posterior cerebral artery (PCA) branches. Exome sequencing detected the heterozygous COL4A5 pathogenic variant c.1871G>A; p.(Gly624Asp), inherited from her hemizygous father, who has Alport syndrome. The proband’s sister, an obligate carrier of the same variant with a history of migraine, was found to have a small brain aneurysm. In the paternal line, the great-grandmother died of a cerebrovascular event in her early 40 s, the great-aunt had a stroke at around 40, and her son died of a cerebrovascular event at 35; the obligate-carrier grandmother had chronic kidney disease and migraine. Conclusions: This COL4A5 variant is usually associated with late-onset Alport syndrome and variable renal involvement, even in obligate carriers, and has not previously been linked to cerebrovascular disease. In the present family, the X-linked clustering of cerebrovascular events raises the possibility that COL4A5 may contribute to cerebrovascular fragility, with an effect that may extend beyond the kidney. These findings suggest that COL4A5 may be relevant in selected families with unexplained cerebrovascular disease, even when renal manifestations are mild or absent.