Clinical Validity Scoring Notes and points | Variant/Case Evidence: c.455C>G p.Ala152Gly Absent from gnomAD v4. De novo in a male pt with microcephaly, DD/ID, feeding difficulties (patient 1, PMID: 32910914) (0.6pts)
p.Ser314_Thr497del Maternally inherited in a female patient with microcephaly, pronounced and long philtrum, short nose, trigonocephaly, mild ID. Mother had OFC mother 50.5 cm (−2.5 SD), low educational level, long philtrum. Variant was de novo in mother. (patient 2, PMID: 32910914) (1pt)
c.97A>G p.Lys33Glu Absent from gnomAD v4. De novo in a female pt with microcephaly, prominent nasal root, protruding tongue, severe ID, pachygyria, thin corpus callosum, spasticity limbs, inability to walk, scoliosis, feeding difficulties, patent foramen ovale. Authors showed that p.Lys33Glu prevented proper formation of the lamina network (patient 3, PMID: 32910914) (1.1pts) De novo in P1, a 1mo male pt with microcephaly, Simplified gyri large ventricles, Increased extraaxial space, seizures, severe DD, dysmorphic features, Recurrent lower respiratory tract infections, gastrostomy. ?pan-hypopit. PMID: 33033404 (0.6pts) De novo in P9, 5-10yo male with microcephaly, Failure to thrive, poor feeding. Constipation. Stereotypical hand movements. Long palpebral fissures, hypertelorism, depressed broad nasal bridge. Pointed chin., Febrile Seizures, GDD. PMID: 33033404 (0.6pts) De novo in P11. 5-10 yo female with microcephaly, Seizures, Hypoplasia/aplasia corpus callosum, Mild/Mod GDD PMID: 33033404 (0.6pts)
c.124C>T p.Arg42Trp Absent from gnomAD v4. De novo in a female patient with microcephaly, dysmorphic features, significant developmental delay, MRI abnormalities, seizures, suspected cortical visual impairment, feeding difficulties, G-tube, recurrent pneumonia. Additional duplication on microarray (15q25.3(85,811,682-86,140,453)x3 pat). Authors showed that p.Lys33Glu prevented proper formation of the lamina network (patient 4, PMID: 32910914) (1.1pts)
c.939+1G>A Absent from gnomAD v4. Adjacent exon is in-frame. 3 affected sibs (one female and 2 male). All had microcephaly and some degree of developmental delay/ID, seizures, hypotonia, scoliosis. The two brothers had cortical visual impairment, feeding difficulties, G-tube, recurrent pneumonia. Father 15% mosaic for the mutation. One brother had an additional finding on microarray (17p13.3 (954,760-1,235,739)x3 (VOUS; CMA-ISCA)). Splice variant identified on trio WES. Mosaicism identified on further analysis. (patient 5-7, PMID: 32910914) (1 pt + 0.5 for sibs: 1.5pts)
c.97_99del p.K33del c.269G>C p.R90P De novo in a 15-20yo M with microcephaly, Mild/Mod GDD , Delayed speech and language development , Hydronephrosis. Failure to thrive Hypothyroidism. PMID: 33033404 (0.6pts)
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Curation Summary | Expand |
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| - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
| The LMNB1 gene is associated with autosomal dominant primary microcephaly. Individuals have a reduced occipitofrontal circumference (OFC) at birth. Affected individuals usually have some level of developmental delay and intellectual disability. They may also have seizures, feeding difficulties, hypotonia, short stature, or dysmorphic features (PMID: 32910914, 33033404). |