Severe microcephalyGene: ARCN1
Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."
Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."
PMID: 33154040 describes another case. "3.5-yr-old Caucasian/Peruvian/Native American boy with microcephaly, severe global developmental delay, and multiple congenital abnormalities. At birth he was documented to have a small ventricular septal defect (which was closed by 3 wk), a patent foramen ovale, rhizomelic shortening of extremities on clinical examination, pectus carinatum, and underdeveloped genitalia including severe penoscrotal hypospadias and cryptorchidism." OFC at birth was just above 10th centile, at 3.5 yr OFC is below 3rd centile but no actual measurements were given. Microarrays identified a 95-kb loss at 12q23.2 including exons 1–4 of the NUP37 gene and exons 1–9 of the PARPBP gene, which were deemed nondiagnostic (neither parents had this deletion). A heterozygous variant was also found in HSPG2 (c.9893 C > T, p. Pro3298Leu). Biallelic variants in this gene is associated with skeletal disorders that did not fit the patient's phenotype and as the patient is heterozygous for a variant in HSPG2 it was deemed that this variant was not causative. WGS identified a de novo splice variant in ARCN1. mRNA studies showed that the variant caused retention of part of an intron in the transcript. The authors deemed the ARCN1 variant as the causative variant in this patient.
Created: 22 Sep 2021, 3:44 p.m. | Last Modified: 22 Sep 2021, 3:57 p.m.
Panel Version: 2.247
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.
The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).
Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Created: 22 Sep 2021, 3:15 p.m. | Last Modified: 23 Sep 2021, 9:11 a.m.
Panel Version: 2.247
Borderline Amber/Green. Microcephaly is a key part of the phenotype but few exact measurements actually reported.
Sources: Expert list
Created: 31 Aug 2020, 11:08 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164) to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
Publications for gene: ARCN1 were set to 27476655
Tag Q3_21_rating was removed from gene: ARCN1. Tag watchlist tag was added to gene: ARCN1.
Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Tag Q3_21_rating tag was added to gene: ARCN1.
gene: ARCN1 was added gene: ARCN1 was added to Severe microcephaly. Sources: Expert list Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARCN1 were set to 27476655 Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164) Review for gene: ARCN1 was set to GREEN gene: ARCN1 was marked as current diagnostic