The Spalt-like transcription factor 1 (SALL1) gene is essential for kidney development. Pathogenic SALL1 variants cause Townes-Brocks syndrome 1 (TBS1), which typically presents with imperforate anus, dysplastic ears, and digital anomalies. However, clinical features vary widely. Some patients present only with dysplastic ears and hearing loss (HL) or with congenital anomalies of the kidney and urinary tract (CAKUT), resembling branchio-oto-renal syndrome (BORS), a presentation referred to as Townes-Brocks branchio-oto-renal-like (TBS BOR-like) syndrome. In this study, we aimed to describe the clinical characteristics of patients with SALL1-related disorders in the Japanese population. We analyzed phenotypes of a nationwide cohort comprising 1108 families with chronic kidney disease (CKD) or mild urinary anomalies, using genetic testing conducted from 2010 to 2024. We identified SALL1 variants in 14 families (20 individuals): seven frameshift, four nonsense, one missense, one exon 2 deletion, and one whole-gene deletion. Ten variants were novel. The median age at diagnosis was 16 years (male:female = 13:7). Dysplastic ears were observed in 45%, HL in 40%, digital anomalies in 40%, and anorectal malformations in 25%. Based on clinical features, eight individuals were diagnosed with TBS1, four with TBS BOR-like syndrome, and seven with non-syndromic CAKUT. One case lacked detailed clinical data. Most variants were truncating and located in exon 2. SALL1-related disorders exhibit broad phenotypic variability. Some cases present with atypical features overlapping with TBS BOR-like syndrome or isolated CAKUT, rather than with typical TBS1. These findings enhance the understanding and diagnosis of SALL1-related disorders.

Asthenozoospermia, characterized by reduced sperm motility, is a common cause of male infertility. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe and genetically heterogeneous form of asthenozoospermia. Over 50 genes have been associated, but approximately half of MMAF cases remain unexplained. DRC1, a gene involved in the nexin-dynein regulatory complex (N-DRC), has been linked to MMAF and primary ciliary dyskinesia (PCD), often with significant variability in clinical presentation. His study aimed to identify novel pathogenic DRC1 variants in MMAF patients, assess their impact on sperm flagellar structure, and evaluate intracytoplasmic sperm injection (ICSI) and pregnancy outcomes. A cohort of 196 non-syndromic MMAF patients was analyzed using whole exome sequencing (WES). Functional validation of candidate variants included immunofluorescence to assess protein expression and transmission electron microscopy (TEM) to identify ultrastructural abnormalities. Assisted reproductive therapy outcomes were also evaluated. WES identified a recurrent homozygous frameshift variant in DRC1 NM_145038.5: c.109dup; p.(Gln37ProfsTer30) in four patients (2%), all of North African origin, none of whom suffer from PCD-related symptoms. The variant caused a complete absence of DRC1 protein in spermatozoa. TEM showed flagellar abnormalities, with 10% of axonemal sections revealing peripheral doublet dissociation, suggesting N-DRC instability. ICSI resulted in a 68.5% fertilization rate, with three out of four couples successfully delivering healthy children. The identification of a novel and recurrent pathogenic DRC1 variant broadens the mutation spectrum associated with MMAF. The absence of systemic PCD symptoms suggests that DRC1 deficiency may primarily affect spermatogenesis. Notably, the phenotypic spectrum might be influenced by the genetic background, varying across populations. Favorable ICSI outcomes, with a 68.5% fertilization rate and successful pregnancies in three out of four couples, highlight the effectiveness of assisted reproductive techniques for patients with this genetic defect.

External Ear Malformations (EEM) continue to be a common malformation seen in the pediatric patient population. This study aims to further elucidate the correlation between EEM and cardiac and renal anomalies. A systematic review and meta-analysis to study the incidence of cardiac and renal anomalies associated with syndromic and isolated (EEM). The literature search spanned multiple databases, including Google Scholar, PubMed, Scopus, Web of Science, and MEDLINE. Studies must be focused on EEM and cardiac and/or renal anomalies. Only articles written in English were included. General study characteristics, number of EEM patients, number of cardiac and renal anomalies and whether cases were syndromic were extracted from the studies. Of 1,058 initial studies, 33 were included for meta-analyses. Mean JBI score for all included studies was 92.06%, indicating acceptable study quality. Interrater reliability was high, with a Cohen kappa score for all studies of 0.94. The resulting pooled prevalence of cardiac abnormalities was 20% [95% CI:13-28%], while renal abnormalities were 13% [95% CI: 7-20%]. The most common anomalies were VSD (3.725%) and renal agenesis (2.04%). The presence of syndrome data across studies was not a significant modifier of prevalence rates. Primary limitation is due to heterogeneity in individual study methodology and reporting standards. These results highlight a higher prevalence of cardiac-related conditions than renal anomalies in patients with both syndromic and non-syndromic EEM in the included studies, underscoring the need for thorough clinical evaluations.

Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.

Cryptorchidism is the condition in which one or both testes have not descended adequately into the scrotum. The congenital form of cryptorchidism is one of the most prevalent urogenital anomalies in male newborns. In the acquired form of cryptorchidism, the testis that was previously descended normally is no longer located in the scrotum. Cryptorchidism is associated with an increased risk of infertility and testicular germ cell tumors. However, data on pubertal progression are less well-established because of the limited number of studies. Here, we aim to review the currently available data on pubertal development in boys with a history of non-syndromic cryptorchidism-both congenital and acquired cryptorchidism. The review is focused on the timing of puberty, physical changes, testicular growth, and endocrine development during puberty. The available evidence demonstrated that the timing of the onset of puberty in boys with a history of congenital cryptorchidism does not differ from that of non-cryptorchid boys. Hypothalamic-pituitary-gonadal hormone measurements showed an impaired function or fewer Sertoli cells and/or germ cells among boys with a history of cryptorchidism, particularly with a history of bilateral cryptorchidism treated with orchiopexy. Leydig cell function is generally not affected in boys with a history of cryptorchidism. Data on pubertal development among boys with acquired cryptorchidism are lacking; therefore, more research is needed to investigate pubertal progression among such boys.