Jens Schallner

Homozygous loss of CHRNA7 on chromosome 15q13.3 causes severe encephalopathy with seizures and hypotonia.

Homozygous Loss of CHRNA7 on Chromosome 15q13.3 Causes Severe Encephalopathy With Seizures and Hypotonia Volker Endris, Karl Hackmann, Teresa M. Neuhann, Ute Grasshoff, Michael Bonin, Ulrich Haug, Gabriele Hahn, Jens C. Schallner, Evelin Schr€ock, Sigrid Tinschert, Gudrun Rappold, and Ute Moog* Department of Molecular Human Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany Institute of Clinical Genetics, Technical University Dresden, Dresden, Germany Institute of Human Genetics, Medical Genetics T€ubingen, T€ubingen, Germany Center for Child Neurology and Social Pediatrics Maulbronn, Maulbronn, Germany Children’s Hospital, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany Institute of Diagnostic Radiology, Department of Pediatric Radiology, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany Department of Human Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt

Background Retinitis pigmentosa in combination with hearing loss can be a feature of different Mendelian disorders. We describe a novel syndrome caused by biallelic mutations in the ‘exosome component 2’ (EXOSC2) gene. Methods Clinical ascertainment of three similar affected patients followed by whole exome sequencing. Results Three individuals from two unrelated German families presented with a novel Mendelian disorder encompassing childhood myopia, early onset retinitis pigmentosa, progressive sensorineural hearing loss, hypothyroidism, short stature, brachydactyly, recognisable facial gestalt, premature ageing and mild intellectual disability. Whole exome sequencing revealed homozygous or compound heterozygous missense variants in the EXOSC2 gene in all three patients. EXOSC2 encodes the ‘ribosomal RNA-processing protein 4’ (RRP4)—one of the core components of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation. Intriguingly, the EXOSC2-associated phenotype shows only minimal overlap with the previously reported diseases associated with mutations in the RNA exosome core component genes EXOSC3 and EXOSC8. Conclusion We report a novel condition that is probably caused by altered RNA exosome function and expands the spectrum of clinical consequences of impaired RNA metabolism.

Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases

&NA; Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood‐onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.

Severe intellectual disability, West syndrome, Dandy–Walker malformation, and syndactyly in a patient with partial tetrasomy 17q25.3

We report on a de novo 0.5 Mb triplication (partial tetrasomy) of chromosome 17q25.3 in a 10‐year‐old girl with severe intellectual disability, infantile seizures (West syndrome), moderate hearing loss, Dandy–Walker malformation, microcephaly, craniofacial dysmorphism, striking cutaneous syndactyly (hands 3–4, feet 2–3), joint laxity, and short stature. The triplication resulted from the unusual combination of a terminal duplication at 17qter and a cryptic translocation of an extra copy of the same segment onto chromosome 10qter. The breakpoint at 17q25.3 was located within the FOXK2 gene. SNP chip analysis suggested that the rearrangement occurred during paternal meiosis involving both paternal chromosomes 17.

New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy

Abstract CACNA1D encodes the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel’s activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.

Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases

The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X‐linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in‐frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug‐resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation.

Skewed X-inactivation in a family with DLG3-associated X-linked intellectual disability

Mutations in DLG3 are a rare cause of non‐syndromic X‐linked intellectual disability (XLID) (MRX90, OMIM *300189). Only ten DLG3 mutations have been reported to date. The majority of female heterozygous mutation carriers was healthy and had random X‐inactivation patterns. We report on an XLID family with a novel DLG3 mutation. The 12‐year‐old male index patient had moderate intellectual disability (ID) and dysmorphic features. The mutation was also present in four female relatives. A maternal aunt had moderate ID and significantly skewed X‐inactivation favorably inactivating the normal DLG3 allele. The probands healthy mother also had skewed X‐inactivation but in the opposite direction (i.e., inactivation of the mutated allele). Two other female relatives had intermediate cognitive phenotypes and random X‐inactivation. This family broadens the mutational and phenotypical spectrum of DLG3‐associated XLID and demonstrates that heterozygous female mutation carriers can be as severely affected as males. Reports of additional families will be needed to elucidate the causes of unfavorable skewing in female XLID patients.

6q22.33 microdeletion in a family with intellectual disability, variable major anomalies, and behavioral abnormalities.

Interstitial deletions on the long arm of chromosome six have been described for several regions including 6q16, 6q22.1, and 6q21q22.1, and with variable phenotypes such as intellectual disability/developmental delay, growth retardation, major and minor facial anomalies. However, an isolated microdeletion of the sub‐band 6q22.33 has not been reported so far and thus, no information about the specific phenotype associated with such a copy number variant is available. Here, we define the clinical picture of an isolated 6q22.33 microdeletion based on the phenotype of six members of one family with loss of approximately 1 Mb in this region. Main clinical features include mild intellectual disability and behavioral abnormalities as well as microcephaly, heart defect, and cleft lip and palate.

Diagnostic value of partial exome sequencing in developmental disorders

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

Primary Microcephaly, Muscle Hypotonia, and Global Developmental Delay: A Case of an Exceptional Clinical Manifestation of Maternally Inherited Mitochondrial T8993T>G Mutation in MT-ATP6 Gene

Objective: The m.8993T>G mutation in the gene MT-ATP6 (MIM:516060) which encodes subunit six of complex V (adenosine triphosphate synthase) of the mitochondrial respiratory chain is one of the more common disease associated mutations in mitochondrial DNA (mtDNA). The mutation is heteroplasmic, occurring together with wild-type mtDNA in affected individuals, and is associated with two different clinical phenotypes: NARP (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome), with the latter usually associated with a high mutation load. Case Report: Here, we report the case of a 2-year-old girl with postnatal primary microcephaly and muscle hypotonia. The infant is the only child of healthy, nonconsanguineous parents. At the age of 6 months, severe development delay appeared. At the age of 20 months, extensive clinical diagnostics revealed elevated serum lactate, brain atrophy in magnetic resonance imaging, and interictal epileptiform discharges. Polymerase chain reaction-restriction fragment length polymorphism analysis detected a high load of the m.8993T>G mutation in blood, confirmed by sequencing. Conclusion: Primary microcephaly is a rare manifestation of mtDNA mutations, and has not yet been described in patients with the m.8993T>G mutation. Genotype--phenotype correlations related to the m.8993T>G mutation seem to be variable, and is not always associated with typical features of MILS or NARP.