NARS1

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0030837

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030837

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030837

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100348

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100348

Submitter: ClinGen

The *NARS1* gene is located on chromosome 18 at 18q21.31 and encodes the cytoplasmic asparaginyl-tRNA synthetase that mediates the charging of the Asn amino acid onto its cognate transfer RNA, which is essential for protein synthesis. *NARS1* was first reported in relation to autosomal recessive neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG) in 2020 (Manole et al., PMID: 32738225). NEDMILG is characterized by global developmental delay, delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance patterns during the precuration. Therefore, the following disease entities have been split into multiple disease entities, autosomal recessive (AR) neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (OMIM:619091) and autosomal dominant (AD) neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) (OMIM:619092). The split curation for AD NEDMILEG has been curated separately with evidence for AR NEDMILEG included here. Eight missense and one nonsense variants that have been reported in six probands in two publications (PMIDs: 32788587, 32738225) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by expression studies, functional alteration of patient cells, and biochemical function (PMIDs: 32788587, 32738225, 32303649). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 6th, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0100348

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030837

Submitter: ClinGen

The *NARS1* gene is located on chromosome 18 at 18q21.31 and encodes the cytoplasmic asparaginyl-tRNA synthetase that mediates the charging of the Asn amino acid onto its cognate transfer RNA, which is essential for protein synthesis. *NARS1* was first reported in relation to autosomal dominant neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) in 2020 (Manole et al., PMID: 32738225). NEDMILEG is characterized by global developmental delay, delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance patterns during the precuration. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant (AD) neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) (OMIM:619092) and autosomal recessive (AR) neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (OMIM:619091). The split curation for AR NEDMILG has been curated separately with evidence for AD NEDMILG included here. Two missense and one nonsense variants that have been reported in eight probands in one publication (PMID: 32738225) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by functional alteration of patient cells, a zebrafish model, and biochemical function (PMIDs: 32738225, 32303649). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 6th, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0100348

Submitter: PanelApp Australia