Inheritance

Autosomal dominant

Prevalence

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen: Sufficient evidence for triplosensitivity, no evidence for haploinsufficiency for adult-onset autosomal dominant demyelinating leukodystrophy

GenCC: Microcephaly - Strong (Franklin and Invitae)

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

• Absent from gnomAD v4.

• Identified in 2 unrelated affected pts (P2 and P3). De novo in 1 and unconfirmed in the other. PMID: 33033404 (0.6 pts + 0.1pts: 0.7pts)

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)

Clinical Validity Points Total

8.4 (stopped here since moderate GDA was reached)

Clinical Validity Classification

At least moderate.

Molecular Mechanism

Loss of function

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

congenital

Severity

Clinical Features

Sources: PMID: 32910914, PMID: 33033404

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

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).

Case ID, Curator name, Date, Jira ticket link

Areesha Salman, SDSM-331, 11/4/24