Expansion of the phenotypic spectrum of KARS1-related disorders to include arthrogryposis multiplex congenita and summary of experiences with lysine supplementation.

There are currently multiple disorders of aminoacyl-tRNA synthetases described, including KARS1-related disorder resulting from dysfunctional lysyl-tRNA synthetases. In this report, we describe four novel KARS1 variants in three affected individuals, two of whom displayed arthrogryposis-like phenotypes, suggestive of phenotypic expansion. We also highlight subjective clinical improvement in one subject following lysine supplementation in conjunction with a protein-fortified diet, suggesting its potential as a novel treatment modality for KARS1-related disorders. This report offers additional insight into the etiology and management of KARS1-related disorders and expands our ability to provide guidance to affected individuals and their families.

Progressive Thrombocytopenia, Splenomegaly, and Abnormal Tone in an Infant With Growth Faltering.

A 4-month-old full-term female presented with growth faltering associated with progressive feeding difficulty, rash, abdominal distension, and developmental delays. She was found to have disconjugate gaze, abnormal visual tracking, mixed tone, bruising, and splenomegaly on examination. Initial workup was notable for thrombocytopenia and positive cytomegalovirus (CMV) immunoglobulin G and immunoglobulin M antibodies. She initially presented to the infectious diseases CMV clinic, where she was noted to have severe malnutrition, prompting referral to the emergency department for hospital admission to optimize nutrition with nasogastric tube feeding and facilitate additional evaluation. An active CMV infection with viruria and viremia was confirmed, but elements of her presentation and workup including brain magnetic resonance imaging were not consistent with isolated CMV infection. To avoid premature diagnostic closure, a multidisciplinary workup was initiated and ultimately established her diagnosis.

A novel 3q interstitial deletion including GATA2 and ZNF148: A case report.

GATA2 and ZNF148 have both been mapped to chromosome 3q. Pathogenic variants in GATA2 have been associated with immunodeficiency and high risk for myelodysplasia, acute myeloid leukemia, and chronic myelomonocytic leukemia. Gain-of-function variants in ZNF148 have previously been suggested as a mechanism for agenesis of the corpus callosum (ACC). Here, we report a novel 10.4 Mb interstitial deletion on 3q12.33q22.1 including GATA2 and ZNF148 in a child with developmental delay, agenesis of the corpus callosum, and vertebral segmentation defects. With this diagnosis, we were able to suggest preemptive referrals to hematology/oncology and allergy/immunology for close monitoring of early myelodysplasia. We also propose a possible link between ZNF148 loss of function variants and ACC.

Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1-further expansion of the phenotypic spectrum.

Osteogenesis imperfecta (OI) is a heritable disorder of bone metabolism characterized by multiple fractures with minimal trauma. Autosomal recessive OI type VIII is associated with biallelic pathogenic variants in P3H1 and classically characterized by skeletal anomalies in addition to significant bone fragility, sometimes presenting with in utero fractures and/or neonatal lethality. P3H1 encodes a collagen prolyl hydroxylase that critically 3-hydroxylates proline residue 986 on the α chain of collagen types I and II to achieve proper folding and assembly of mature collagen and is present in a complex with CRTAP and CypB. Most individuals with OI type VIII have had biallelic predicted loss-of-function variants leading to reduced or absent levels of P3H1 mRNA. The reported missense variants have all fallen in the catalytic domain of the protein and are thought to be associated with a milder phenotype. Here, we describe an infant presenting with five long bone fractures in the first year of life found to have a novel missense variant in trans with a nonsense variant in P3H1 without any other bony anomalies on imaging. We hypothesize that missense variants in the catalytic domain of P3H1 lead to decreased but not absent hydroxylation of Pro986, with preserved KDEL retention signal and complex stability, causing an attenuated phenotype.

Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding.

We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1, in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells.

Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype.

BACKGROUND: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.

Clinical Utility of Genetic Testing in the Precision Diagnosis and Management of Pediatric Patients with Kidney and Urinary Tract Diseases.

Background: As genetic testing increasingly integrates into the practice of nephrology, our understanding of the basis of many kidney disorders has exponentially increased. Given this, we recently initiated a Renal Genetics Clinic (RGC) at our large, urban children's hospital for patients with kidney disorders. Methods: Genetic testing was performed in Clinical Laboratory Improvement Amendments-certified laboratories using single gene testing, multigene panels, chromosomal microarray, or exome sequencing. Results: A total of 192 patients were evaluated in this clinic, with cystic kidney disease (49/192) being the most common reason for referral, followed by congenital anomalies of the kidney and urinary tract (41/192) and hematuria (38/192). Genetic testing was performed for 158 patients, with an overall diagnostic yield of 81 out of 158 (51%). In the 16 out of 81 (20%) of patients who reached a genetic diagnosis, medical or surgical treatment of the patients were affected, and previous clinical diagnoses were changed to more accurate genetic diagnoses in 12 of 81 (15%) patients. Conclusions: Our genetic testing provided an accurate diagnosis for children and, in some cases, led to further diagnoses in seemingly asymptomatic family members and changes to overall medical management. Genetic testing, as facilitated by such a specialized clinical setting, thus appears to have clear utility in the diagnosis and counseling of patients with a wide range of kidney manifestations.

Sudden infant death with dysgenesis of the testes syndrome in a non-Amish infant: A case report.

Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In this report, we describe a non-Amish, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Initial testing showed that she had a 46,XY chromosome complement, and chromosomal microarray showed a significant absence of heterozygosity (AOH) totalling roughly 600 Mb across multiple different chromosomes, indicating consanguinity. Further workup with exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52) consistent with a diagnosis of SIDDT, explaining many of her clinical features. However, she was also noted to have a mild T-cell lymphopenia and developed intractable epilepsy after hospital discharge. These features have not previously been reported in SIDDT and may represent phenotypic expansion. To our knowledge, this patient is the 22nd case of SIDDT to be reported in the literature, and the first to be of non-Amish heritage.

GNA11 brain somatic pathogenic variant in an individual with phacomatosis pigmentovascularis.

OBJECTIVE: To describe the findings of histopathology and genotyping studies in affected brain tissue from an individual with phacomatosis pigmentovascularis (PPV). METHODS: A retrospective chart review of a 2-year 10-month-old male with a clinical diagnosis of PPV cesiomarmorata (or type V) was performed. Clinical features, brain imaging and histopathology findings, and genotyping studies in his affected brain tissue are summarized. RESULTS: The proband had a clinically severe neurologic phenotype characterized by global developmental delay, generalized hypotonia, and recurrent episodes of cardiac asystole in the setting of status epilepticus. A somatic pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys) was detected in his skin tissue but not in blood (previously published). He underwent an urgent left posterior quadrantectomy for his life-threatening seizures. Histopathology of resected brain tissue showed an increase in leptomeningeal melanocytes and abnormal vasculature, and the exact pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys), previously isolated from his skin tissue but not blood, was detected in his resected brain tissue. CONCLUSIONS: The finding of this variant in affected skin and brain tissue of our patient with PPV supports a unifying genetic diagnosis of his neurocutaneous features.

Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review.

BACKGROUND: Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data. STUDY DESIGN/METHODS: We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected. RESULTS: The median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT. CONCLUSION: In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF.

The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.