Potential oligogenic disease of mental retardation, short stature, spastic paraparesis, and osteopetrosis

Figures & data

Figure 1 Family pedigree.

Figure 2 Neuroimaging of the affected subjects.

Notes: (A) High T1 signal in the basal ganglia. (B) Axial FLAIR sequence demonstrates bilateral periventricular confluent high FLAIR signal intensity. (C) Axial CT scan shows bilateral basal ganglia calcifications. (D) Coronal T1-WI shows bilateral symmetric high T1 signal of the basal ganglia compatible with calcification. (E) Coronal FLAIR demonstrates no significant abnormal white matter signal. (F) Midsagittal T1-WI demonstrates normal appearance of the midline corpus callosum.
Abbreviations: CT, computed tomography; FLAIR, fluid-attenuated inversion recover.

Table 1 Clinical features of the severely affected sister (111-4)

Short stature

Cognitive and language delay

Micrognathia

Low set ears

Frontal bossing

Triangular face

Widely spaced teeth

Spastic

Dystonic posture of extremities

Weakness

Mild metabolic acidosis

Calcifications in basal ganglia nuclei (Figure 2A, C)

Thinning of corpus callosum and signal change in periventricular white matter (Figure 2B)

Generalized increased sclerosis of the bony skeleton with mild metaphyseal expansion/flaring of the long tubular bones and mild bowing deformity of the short tubular bones of the hands and feet

Figure 3 Photographs of affected subject (111-2).

Notes: (A, B) (111-2) is an affected sister with short stature, mild cognitive delay, micrognathia, low set ears, frontal bossing, and widely spaced teeth.

Table 2 Clinical features of the moderately affected sister (111-2)

Short stature

Mild cognitive delay

Micrognathia

Low set ears

Frontal bossing

Triangular face

Widely spaced teeth

Calcifications in basal ganglia nuclei (Figure 2A, B)

Generalized increased sclerosis of the bony skeleton

Table 3 Pathogenic variants in disease genes related to clinical phenotype of the index case

Disease	Inheritance pattern	Gene	Position	Isoform	Location	Nucleotide	Amino acid	Zygosity	References/comments
3-Methylcrotonyl- CoA carboxylase 2 deficiency [MIM:210210]	AR	MCCC2	Chr5:70936845	NM_022132	Exon11	c.1015G>A	p.V339M	Homozygous	Confirmed by Sanger sequencing. Both parents are heterozygous. Unaffected sibling is heterozygous
Osteopetrosis, autosomal recessive 3, with renal tubular acidosis [MIM:259730]	AR	CA2	Chr8:86377699	NM_000067	Intron2	c.232+1G>A	N/A	Homozygous	Confirmed by Sanger sequencing. Both parents are heterozygous
Spastic paraplegia 11, autosomal recessive [MIM:604360]	AR	SPG11	Chr15:44865850	NM_25137	Exon32	c.6100C>T	p.R2034X	Homozygous	Confirmed by Sanger sequencing. Both parents are heterozygous
Alazmai syndrome [MIM:612291]	AR	LARP7	Chr4:113570809	NM_182896	Exon9	c.1261G>A	p.V421l	Homozygous	Novel variant. Confirmed by Sanger sequencing. Both parents are heterozygous

Abbreviation: AR, autosomal recessive.

Table 4 Summary of the whole exome sequencing of the family members

Mutation	The index case (111-4)	Father (11-2)	Mother (11-3)	Moderately affected sister (111-2)	Nonaffected sister (111-3)
A homozygous c.1015G>A (p.V339M) pathogenic variant in the MCCC2 gene	Homozygous	Heterozygous	Heterozygous	Homozygous	Heterozygous
A homozygous c.232+1G>A pathogenic variant in the CA2 gene	Homozygous	Heterozygous	Heterozygous	Homozygous	Heterozygous
A homozygous c.6100C>T (p.R2034X) pathogenic variant in the SPG11 gene	Homozygous	Heterozygous	Heterozygous	Heterozygous	Negative
A homozygous c.1261G>A (p.V421) variant of unknown clinical significance (VUS) in the LARP7	Homozygous	Heterozygous	Heterozygous	Homozygous	Heterozygous