Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

American Journal of Medical Genetics Part AVolume 182, Issue 7 p. 1541-1546 ISSUE INFORMATIONFree Access Table of Contents, Volume 182A, Number 7, July 2020 First published: 20 June 2020 https://doi.org/10.1002/ajmg.a.61236AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume182, Issue7July 2020Pages 1541-1546 RelatedInformation

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient's phenotype was complicated by a dual diagnosis. More recently, an article describing a set of affected siblings was published. We describe three, previously unreported, patients showing clinical variability for this newly defined syndrome. The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features. The authors suggest the delineation of an acronym using the gene name and common features seen across the majority of patients reported so far. This new nomination, MED-DOCS, may help clinicians to recognize, suspect, and remember this novel syndrome.

BACKGROUND:Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay. METHODS:Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members. RESULTS:We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss. CONCLUSIONS:While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

The mechanism of inheritance of sporadically occurring Duchenne muscular dystrophy has been investigated in 42 families, using carrier detection methods and genetic evaluation. Our studied find that serum CPK detects 72% of female carriers of DMD. Quantitative LDH and/or its isozymes were not found to be a useful means of carrier detection, as reported by Roses et al. (1977). Employing family pedigree data and CPK carrier testing, we determined by Bayesian methods the probability that the mother and maternal grandmother in these families were DMD carriers. These studies revealed 23 families (Category I) with no evidence for DMD carriers, 11 families (Category II) in which the mother was found to be a carrier, and 3 families (Category III) in which both mother and maternal grandmother were found to be carriers. Nineteen of the 42 families have a greater than 83% probability that the sporadic DMD case arose by mutation in a maternal gamete. This finding is in good agreement with the theoretically expected 1/3 of DMD cases arising by new mutation.

We observed within 6 months 4 infants with severe hyperammonemia, only one of whom has a proven enzyme defect. Of the remaining 3, all appeared normal at birth with Apgars >8. All had blood NH3 >2000 μg/dl, severe neurologic impairment, seizures, and complete apnea. All were treated vigorously with peritoneal dialysis, protein restriction, and high glucose infusion. Case 1 was a 3110 gm male who required ventilatory assistance at age 4 h for respiratory distress. Initial NH3 was 3000 μg/dl at age 30 h. The patient died of respiratory distress at age 8 d with a falling blood NH3. Biochemical studies revealed no evidence of urea cycle defect or organic acid disorder. Case 2 was a 2950 gm female who fed poorly, had irregular breathing, and was found to have a blood NH3 of 2700 μg/dl at age 44 h. Blood NH3 was normal by age 6 d; she tolerated normal protein intake and appears developmentally normal at age 4 m. Case 3 was a 2100 gm female product of a 35 wk gestation. Ventilatory assistance for respiratory distress was needed at age 10 h and initial NH3 was 3000 μg/dl at age 30 h. Blood NH3 was normal by age 7 d. No inborn error was diagnosed, but the patient has not been challenged yet with normal protein intake. Case 2 and probably Case 1 represent severe transient hyperammonemia in term infants. Cases 1 and 3 were similar with early development of respiratory distress and ↑NH3 prior to feeding. We believe neonatal hyperammonemia is more common than is generally recognized.