Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies.

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease.

Craniofacial developmental biology in the single-cell era.

The evolution of a unique craniofacial complex in vertebrates made possible new ways of breathing, eating, communicating and sensing the environment. The head and face develop through interactions of all three germ layers, the endoderm, ectoderm and mesoderm, as well as the so-called fourth germ layer, the cranial neural crest. Over a century of experimental embryology and genetics have revealed an incredible diversity of cell types derived from each germ layer, signaling pathways and genes that coordinate craniofacial development, and how changes to these underlie human disease and vertebrate evolution. Yet for many diseases and congenital anomalies, we have an incomplete picture of the causative genomic changes, in particular how alterations to the non-coding genome might affect craniofacial gene expression. Emerging genomics and single-cell technologies provide an opportunity to obtain a more holistic view of the genes and gene regulatory elements orchestrating craniofacial development across vertebrates. These single-cell studies generate novel hypotheses that can be experimentally validated in vivo. In this Review, we highlight recent advances in single-cell studies of diverse craniofacial structures, as well as potential pitfalls and the need for extensive in vivo validation. We discuss how these studies inform the developmental sources and regulation of head structures, bringing new insights into the etiology of structural birth anomalies that affect the vertebrate head.

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Gestational diabetes mellitus induces congenital anomalies of the kidney and urinary tract in mice by altering RET/MAPK/ERK pathway.

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.

DLG2 intragenic exonic deletions reinforce the link to neurodevelopmental disorders and suggest a potential association with congenital anomalies and dysmorphism.

PURPOSE: Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. METHODS: Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. RESULTS: A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. CONCLUSION: Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism.

Three-Year Post-Neonatal Intensive Care Unit Health Care Utilization Among Infants with Congenital Anomalies.

OBJECTIVE: To describe 3-year post-neonatal intensive care unit (NICU) health care use among children with congenital anomalies discharged home from a level IV NICU. STUDY DESIGN: Retrospective chart review of children with congenital anomalies enrolled in a previous prospective cohort study from 201 to 2020. We assessed hospital readmission rate, number of surgeries, and durable medical equipment (DME) use by type of anomaly. RESULTS: Among 166 infants enrolled in the original study, 158 survived to NICU discharge. One-third of the cohort had a genetic anomaly. Six of 158 patients (4%) died before 3 years of age. More than one-half the children were readmitted within the first 2 years of life, and one-third were readmitted in the third year of life. Readmissions were greatest for those with multiple, musculoskeletal, and central nervous system anomalies and lowest for abdominal-wall defects. Approximately one-half the children underwent surgeries, and this proportion remained constant over the 3-year time. Sixty-two percent of patients received DME at discharge, with gastrostomy tubes being the most common. Gastrostomy tubes were still present in 75% of the patients at 3 years of age. CONCLUSION: Children with congenital anomalies are at risk for increased health care use during early childhood. Those with multiple anomalies, a genetic syndrome, musculoskeletal, and central nervous system anomalies and those discharged with DME are at greatest risk whereas those with abdominal-wall defects are at lowest risk. Provider awareness, high-quality discharge training, parent psychological support, greater assimilation of families in the NICU, and telehealth may be some strategies to better support these families.

Isolated Hydronephrosis and Urinary Tract Infection by Two Years of Age: A Population-Based Study.

OBJECTIVE: To evaluate the risk for urinary tract infection (UTI) in infants with isolated hydronephrosis (IH). STUDY DESIGN: A retrospective, population-based study including all infants insured by Clalit Health Services and followed from birth to age 2 years in 3 regions of central Israel. Infants were divided into 3 groups based on electronic medical record diagnoses by age 6 months: (1) control: no urological diagnosis; (2) IH; and (3) complicated urological diagnosis (CUD): any additional nephrological/urological diagnosis with/without HN. The primary outcome was a diagnosis of UTI in the first 2 years of life. RESULTS: The cohort included 340 619 infants (52% male): 333 920 controls, 4369 with IH, and 2331 with CUD. Infants with IH were associated with a greater risk for UTI than control patients (17% vs 4%, P < .001). UTI risk for a male infant with IH was greater than for a female infant in the control group (12.6% vs 6.5%, P < .001). In a multivariable logistic regression analysis, both IH (OR 7.04; 95% CI 6.46-7.66) and CUD (OR 14.9; 95% CI 13.6-16.4) were independently associated with UTI. CONCLUSION: Infants with IH are at a greater risk for UTI in the first 2 years of life, supporting the recommendation for a high index of suspicion for UTI in this population.

Long-Term Outcomes, Including Fetal and Neonatal Prognosis, of Renal Oligohydramnios: A Retrospective Study over 22 Years.

OBJECTIVE: To assess the long-term outcome of renal oligohydramnios and risk factors for fetal, neonatal, and postneonatal death. STUDY DESIGN: This retrospective cohort study included fetuses with prenatally detected renal oligohydramnios between 2002 and 2023. Patients who were lost to follow-up were excluded. Fetal, neonatal, and long-term outcomes were evaluated, and their risk factors were analyzed. RESULTS: Of 131 fetuses with renal oligohydramnios, 46 (35%) underwent a termination of pregnancy, 11 (8%) had an intrauterine fetal death, 26 (20%) had a neonatal death, nine (7%) had a postneonatal death, and 39 (30%) survived. Logistic regression analyses showed that an earlier gestational age at onset (OR 1.16, 95% CI 1.01-1.37) was significantly associated with intrauterine fetal death; anhydramnios (OR 12.7, 95% CI 1.52-106.7) was significantly associated with neonatal death as a prenatal factor. Although neonatal survival rates for bilateral renal agenesis, bilateral multicystic dysplastic kidney (MCDK), and unilateral MCDK with contralateral renal agenesis were lower than for other kidney diseases, 1 case of bilateral renal agenesis and two of bilateral MCDK survived with fetal intervention. Kaplan-Meier overall survival rates were 57%, 55%, and 51% for 1, 3, and 5 years, respectively. In the Cox proportional hazards model, birth weight <2000 g (hazard ratio 7.33, 95% CI 1.48-36.1) and gastrointestinal comorbidity (hazard ratio 4.37, 95% CI 1.03-18.5) were significant risk factors for postneonatal death. CONCLUSION: Long-term survival following renal oligohydramnios is a feasible goal and its appropriate risk assessment is important.

Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene.

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.

Outcome of partial agenesis of corpus callosum.

BACKGROUND: The diagnosis of corpus callosum anomalies by prenatal ultrasound has improved over the last decade because of improved imaging techniques, scanning skills, and the routine implementation of transvaginal neurosonography. OBJECTIVE: Our aim was to investigate all cases of incomplete agenesis of the corpus callosum and to report the sonographic characteristics, the associated anomalies, and the perinatal outcomes. STUDY DESIGN: We performed a retrospective analysis of cases from January 2007 to December 2017 with corpus callosum anomalies, either referred for a second opinion or derived from the prenatal ultrasound screening program in a single tertiary referral center. Cases with complete agenesis were excluded from the analysis. Standardized investigation included a detailed fetal ultrasound including neurosonogram, fetal karyotyping (standard karyotype or array comparative genomic hybridization) and fetal magnetic resonance imaging. The pregnancy outcome was collected, and pathologic investigation in case of termination of the pregnancy or fetal or neonatal loss was compared with the prenatal findings. The pregnancy and fetal or neonatal outcomes were reported. The neurologic assessment was conducted by a pediatric neurologist using the Bayley Scales of Infant Development-II and the standardized Child Development Inventory when the Bayley investigation was unavailable. RESULTS: Corpus callosum anomalies were diagnosed in 148 cases during the study period, 62 (41.9%) of which were excluded because of complete agenesis, and 86 fetuses had partial agenesis (58.1%). In 20 cases, partial agenesis (23.2%) was isolated, whereas 66 (76.7%) presented with different malformations among which 29 cases (43.9%) were only central nervous system lesions, 21 cases (31.8%) were non-central nervous system lesions, and 16 cases (24.3%) had a combination of central nervous system and non-central nervous system lesions. The mean gestational age at diagnosis for isolated and non-isolated cases was comparable (24.29 [standard deviation, 5.05] weeks and 24.71 [standard deviation, 5.35] weeks, respectively). Of the 86 pregnancies with partial agenesis, 46 patients opted for termination of the pregnancy. Neurologic follow-up data were available for 35 children. The overall neurologic outcome was normal in 21 of 35 children (60%); 3 of 35 (8.6%) showed mild impairment and 6 of 35 (17.1%) showed moderate impairment. The remaining 5 of 35 (14.3%) had severe impairment. The median duration of follow-up for the isolated form was 45.6 months (range, 36-52 months) and 73.3 months (range, 2-138 months) for the nonisolated form. CONCLUSION: Partial corpus callosum agenesis should be accurately investigated by neurosonography and fetal magnetic resonance imaging to describe its morphology and the associated anomalies. Genetic anomalies are frequently present in nonisolated cases. Efforts must be taken to improve ultrasound diagnosis of partial agenesis and to confirm its isolated nature to enhance parental counseling. Although 60% of children with prenatal diagnosis of isolated agenesis have a favorable prognosis later in life, they often have mild to severe disabilities including speech disorders at school age and behavior and motor deficit disorders that can emerge at a later age.

Temporal Trends of Neonatal Surgical Conditions in Texas and Accessibility to Pediatric Surgical Care.

INTRODUCTION: Texas consistently accounts for approximately 10% of annual national births, the second highest of all US states. This temporal study aimed to evaluate incidences of neonatal surgical conditions across Texas and to delineate regional pediatric surgeon accessibility. METHODS: The Texas Birth Defects Registry was queried from 1999 to 2018, based on 11 well-established regions. Nine disorders (30,476 patients) were identified as being within the operative scope of pediatric surgeons: biliary atresia (BA), pyloric stenosis (PS), Hirschsprung's disease, stenosis/atresia of large intestine/rectum/anus, stenosis/atresia of small intestine, tracheoesophageal fistula/esophageal atresia, gastroschisis, omphalocele, and congenital diaphragmatic hernia. Annual and regional incidences were compared (/10,000 births). Statewide pediatric surgeons were identified through the American Pediatric Surgical Association directory. Regional incidences of neonatal disorder per surgeon were evaluated from 2010 to 2018 as a surrogate for provider disparity. RESULTS: PS demonstrated the highest incidence (14.405/10,000), while BA had the lowest (0.707/10,000). Overall, incidences of PS and BA decreased significantly, while incidences of Hirschsprung's disease and small intestine increased. Other diagnoses remained stable. Regions 2 (48.24/10,000) and 11 (47.79/10,000) had the highest incidence of neonatal conditions; Region 6 had the lowest (34.68/10,000). Three rural regions (#2, 4, 9) lacked pediatric surgeons from 2010 to 2018. Of regions with at least one surgeon, historically underserved regions (#10, 11) along the Texas-Mexico border consistently had the highest defect per surgeon rates. CONCLUSIONS: There are temporal and regional differences in incidences of neonatal conditions treated by pediatric surgeons across Texas. Improving access to neonatal care is a complex issue that necessitates collaborative efforts between state legislatures, health systems, and providers.

A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Maternal and fetal outcomes of antiepileptic treatments during pregnancy: A retrospective study.

INTRODUCTION: Epilepsy is a disease that affects a significant proportion of the female population worldwide. The management of anti-seizure medications during pregnancy and the potential adverse outcomes to both the mother and fetus represent a significant challenge. This retrospective study aimed to evaluate the impact of anti-seizure medications during pregnancy by comparing maternal and fetal outcomes between pregnant women with and without epilepsy. METHODS: A total of 242 participants were analysed, including 112 with epilepsy and 130 healthy pregnant controls. Maternal age, medical history, seizure characteristics, use of anti-seizure medications, and pregnancy history were recorded. Maternal and fetal complications, delivery modes, and perinatal outcomes were evaluated. RESULTS: A total of 242 patients, including 112 (46.3 %) pregnant women with epilepsy and 130 (53.7 %) healthy pregnant women, were included in the study. Among pregnant patients with epilepsy, 4 (3.5 %) did not use anti-seizure medications, 79 (70.5 %) received monotherapy, and 29 (25.8 %) received polytherapy. The rates of pregnancy termination, spontaneous abortion, and maternal and fetal complications were significantly higher in pregnant women with epilepsy (p = 0.045, p = 0.045, p < 0.001, and p = 0.016, respectively). Folic acid use, planned pregnancy rate and postpartum breastfeeding rate were all statistically lower in pregnant women with epilepsy (p < 0.001, p < 0.001, p < 0.001, respectively). The rates of intensive care unit stay, infants with birth weight less than 2500 g, congenital malformations, and preterm births were significantly higher in babies born to pregnant women with epilepsy (p < 0.001, p = 0.047, p = 0.003, and p = 0.051, respectively). Gestational diabetes mellitus was observed in 4 (13.8 %) and congenital malformations in 4 (14.3 %) of the pregnant women with epilepsy who received polytherapy, and in both cases these rates were statistically higher than those of pregnant women with epilepsy who received monotherapy (p = 0.048 and p = 0.004, respectively). DISCUSSION: This study demonstrated that pregnancies among women affected by epilepsy have significantly higher rates of maternal and fetal complications, spontaneous abortions, and premature births. Polytherapy with anti-seizure medications is associated with an increased risk of gestational diabetes and congenital anomalies. Notably, folic acid use, planned pregnancy, and postpartum breastfeeding were less common in patients with epilepsy. The most commonly prescribed anti-seizure medications were levetiracetam and lamotrigine. Caesarean section is a common mode of delivery in pregnancies of mothers with epilepsy. CONCLUSION: These results suggest that epilepsy increases both maternal and fetal complications during pregnancy. Furthermore, the use of anti-seizure medications appears to have a significant impact on pregnancy outcomes. Our findings highlight the need for comprehensive management strategies and informed decision making to reduce risks and optimise maternal and fetal outcomes among women with epilepsy.

Ocular manifestations of congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common birth defects worldwide and a major cause of kidney failure in children. Extra-renal manifestations are also common. This study reviewed diseases associated with the Genomics England CAKUT-associated gene panel for ocular anomalies. In addition, each gene was examined for expression in the human retina and an ocular phenotype in mouse models using the Human Protein Atlas and Mouse Genome Informatics databases, respectively. Thirty-four (54%) of the 63 CAKUT-associated genes (55 'green' and 8 'amber') had a reported ocular phenotype. Five of the 6 most common CAKUT-associated genes (PAX2, EYA1, SALL1, GATA3, PBX1) that represent 30% of all diagnoses had ocular features. The ocular abnormalities found with most CAKUT-associated genes and with five of the six commonest were coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataract. Seven of the CAKUT-associated genes studied (11%) had no reported ocular features but were expressed in the human retina or had an ocular phenotype in a mouse model, which suggested further possibly-unrecognised abnormalities. About one third of CAKUT-associated genes (18, 29%) had no ocular associations and were not expressed in the retina, and the corresponding mouse models had no ocular phenotype. Ocular abnormalities in individuals with CAKUT suggest a genetic basis for the disease and sometimes indicate the affected gene. Individuals with CAKUT often have ocular abnormalities and may require an ophthalmic review, monitoring, and treatment to preserve vision.

Genetics of kidney disorders in Phelan-McDermid syndrome: evidence from 357 registry participants.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. METHODS: We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. RESULTS: Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5 Mb and 400 Kb from the telomere. CONCLUSIONS: The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.

Brain and spine malformations and neurodevelopmental disorders in a cohort of children with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.

Reference values for urinary protein, albumin, beta 2-microglobulin, and the alpha 1-microglobulin-to-creatinine ratio in Japanese children.

BACKGROUND: The importance of the ratio of creatinine to urinary protein, albumin, and low-molecular weight protein as a urinary marker in chronic kidney disease patients is widely recognized. However, no reference values have hitherto been established for these markers in Japanese children. The present study aimed to establish the reference values for these urinary markers in Japanese children. METHODS: The first morning urine was randomly collected from 1712 pupils aged ≥ 3 to < 18 years during school and kindergarten mass urinary screenings. The upper limit of the reference values was set at the 97.5th percentile of the creatinine ratio per marker. RESULTS: The urinary protein-to-creatinine ratio (PCR), urinary albumin-to-creatinine ratio (ACR), urinary beta 2-microglobulin-to-creatinine ratio (BMCR), and urinary alpha 1-microglobulin-to-creatinine ratio (AMCR) showed an age-related decrease at the 50th percentile reflecting an age-related increase in urinary creatinine. The appropriate reference value for the PCR and ACR was 0.12 g/gCr and 35 mg/gCr, respectively, in the entire cohort. The appropriate reference value for the BMCR was 0.5 µg /mgCr for age ≥ 3 to < 6 years and 0.35 µg/mgCr for age 6 years or older. The appropriate reference value for the AMCR was 5.0 µg/mgCr for age ≥ 3 to < 6 years and 3.5 µg /mgCr for age 6 years or older. CONCLUSION: The present study was the first to determine appropriate reference values for the PCR, ACR, BMCR, and AMCR based on an analysis of the first morning urine samples of a large number of children.

Determinants of externally visible birth defects among perinatal deaths at Adama Comprehensive Specialized Hospital: a case-control study.

BACKGROUND: Birth defects (BDs) are the major causes of infant morbidity and mortality in both developed and developing countries. Regardless of their clinical importance, few studies on predisposing factors have been conducted in Ethiopia. However, due to a lack of advanced diagnostic materials, we only considered the externally visible BDs. OBJECTIVE: To assess the determinants of externally visible birth defects among perinatal deaths at Adama Comprehensive Specialized Hospital. METHODS: A retrospective unmatched case-control study design was conducted from November 01 to 30, 2021. The sample size was determined by Epi Info version 7 software considering sample size calculation for an unmatched case-control study. A total of 315 participants (63 cases, and 252 controls) were selected by simple random sampling. Data were collected by an open data kit (ODK) and transported to a statical package for social sciences (SPSS) version 26 software for analysis. The bivariate followed by multivariable logistic regression analyses were done to determine the factors associated with the BD. RESULTS: This study showed that drinking alcohol during pregnancy (AOR = 6.575; 95% CI: 3.102,13.937), lack of antenatal care (ANC) follow-up during pregnancy (AOR = 2.794; 95% CI: 1.333, 5.859), having a history of stillbirth in a previous pregnancy (AOR = 3.967; 95% CI: 1.772, 8.881), exposure to pesticides during pregnancy (AOR = 4.840; 95% CI: 1.375, 17.034), having a history of BDs in a previous pregnancy (AOR = 4.853; 95% CI: 1.492, 15.788), and lack of folic acid supplementation during early pregnancy (AOR = 4.324; 95% CI: 2.062, 9.067) were significant determinants of externally visible BDs among perinatal deaths. CONCLUSION: In this study, alcohol use, exposure to pesticides, and lack of folic acid supplementation during pregnancy were identified as the major determinants of externally visible BDs among perinatal deaths. Thus, health education regarding the associated factors of BDs and their preventive strategies should be given to pregnant mothers.